Drug delivery methods and systems

ABSTRACT

A two-part bioactive agent delivery system, the system including a disposable part comprising an agent reservoir, a bolus chamber, the volume of the bolus chamber being less than the volume of the agent reservoir, an agent outlet, and a valve having a first position communicating the agent reservoir with the bolus chamber and a second position communicating the bolus chamber with the outlet; and a reusable part including a valve driver, a power source and control electronics, the control electronics being adapted to control the valve driver to actuate the valve to deliver bioactive agent from the agent reservoir to the agent outlet; the system further having a spring extending between the agent reservoir piston and a surface of the reusable part or of the disposable part to pressurize the agent reservoir when the spring is compressed and the agent reservoir contains a quantity of bioactive agent.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/699,382, filed Sep. 8, 2017, which is a divisional of U.S.application Ser. No. 15/009,683, filed Jan. 28, 2016, which claims thebenefit of U.S. Provisional Application No. 62/108,959, filed Jan. 28,2015; U.S. Provisional Application No. 62/132,436, filed Mar. 12, 2015;and U.S. Provisional Application No. 62/263,516, filed Dec. 4, 2015, thedisclosures of which are incorporated by reference in their entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

BACKGROUND

Medicinal drugs are given to people to manage or improve their healthfor a variety of reasons, such as to prevent or treat a medicalcondition or disease such as diabetes, Parkinson's disease, ulcerativecolitis, or to manage nicotine or another addiction or dependency, or tomanage pain.

Some medicinal drugs are rapidly metabolized by the body; multiple dosesof the drug over a period of time are therefore often needed to providea desired effect. In addition to having desired preventative ortherapeutic effects, medicinal drugs can also have negative side-effectson the body that can range from irritating to life-threatening. Aperson's body can also develop tolerance to a drug and experience adiminished response to the drug after taking it for a period of time andrequire higher doses to have an effect, resulting in increased drug useand additional side-effects. Despite their negative side-effects, aperson takes a medicinal drug because, on the whole, the drug causesmore good than harm. It is beneficial to a person taking a drug tominimize the amount of drug they take to prevent or minimize toleranceand other unwanted side-effects while still receiving the desiredtherapeutic effect from the drug.

Tobacco use (such as smoking) causes serious health problems and canlead to premature death. According to the United States Center forDisease Control (CDC), tobacco use causes more than 5 million deaths peryear as well as contributing to the development of serious illnessessuch as cancer, diabetes, heart disease, lung disease (bronchitis,chronic airway destruction, emphysema), and stroke. Despite anti-smokingadvertising campaigns, legislation, taxation, and development of smokingcessation products to stop or prevent people from using tobacco, tobaccosales remains a multibillion dollar industry, generating an estimated$35 billion dollars per year in profits. Tobacco initially causesphysical and mood-altering effects that are temporarily pleasing. It isdifficult for a person to stop using a tobacco product, because tobaccocontains nicotine. Nicotine is highly addictive, and not having thenicotine causes harsh withdrawal symptoms. It is very difficult for aperson to overcome a nicotine addiction and stop smoking.

Medicinal drugs can be taken by tobacco users to help them to overcometheir nicotine addiction and stop using tobacco. Some products to help aperson stop smoking contain small amounts of nicotine as a medicinaldrug to minimize withdrawal symptoms and gradually wean a person fromtheir nicotine addiction. Medicinal smoking cessation drugs such asnicotine have to be taken over an extended period of time (often overthe course of many months) to give the body time to adjust to havingless nicotine. Medicinal drugs, medical devices and other products,including smoking cessation products, are regulated in the United Statesby the U.S. Food and Drug Administration (FDA). FDA approved products onthe market to help a person quit smoking include various medicinal drugsthat require a doctor's prescription as well as over-the-counterproducts. These products include capsules or tablets, gums, inhalers,lozenges, nasal sprays, and skin patches. These products have thus farbeen inadequate to get people to stop smoking: 68.9% of adult cigarettesmokers say they want to stop smoking, and every year some 42.7% make anattempt to stop smoking, but are unsuccessful.

These existing smoking cessation products and other therapeutic andprophylactic treatments for health issues suffer from a variety ofproblems. They may be inconvenient or socially awkward to use. They mayrequire careful and troublesome tracking of when they were used and howmuch was used to prevent overdosing. They may act too slowly after beingadministered and not produce a desired effect when it's needed. They maynot be readily available when they are needed (such as while a person issleeping). None have been wholly effective to for preventing or treatingvarious medical or other conditions. Smoking, for example, remains asignificant health and social problem.

What are needed are new and improved systems, devices and methods fordelivering drugs and other bioactive agents, such as smoking cessationagents, to a person. Provided herein are systems, devices and methodsfor delivering a drug or other bioactive agent to an individual. Thesemay be useful for treating or preventing a medical condition, disease,addiction, dependency or for managing pain and may be especially usefulfor helping a tobacco user to stop using tobacco. New and improvedsystems with increased safety and improved efficiency for delivering thedrugs and other bioactive agents are also desired and disclosed herein.

SUMMARY OF THE DISCLOSURE

The present invention relates generally to systems for deliveringbioactive agents and methods for using the systems to delivery bioactiveagents.

One aspect of the invention provides a two-part bioactive agent deliverysystem, the system including a disposable part comprising an agentreservoir (having a volume, e.g., of less than about 3 ml.), the agentreservoir having a piston movably disposed in a chamber, a bolus chamber(having a volume, e.g., of less than about 0.5 ml), the bolus chamberhaving a piston movably disposed in a chamber, the volume of the boluschamber being less than the volume of the agent reservoir, an agentoutlet, and a valve having a first position communicating the agentreservoir with the bolus chamber and a second position communicating thebolus chamber with the outlet; and a reusable part including a valvedriver, a power source and control electronics, the control electronicsbeing adapted to control the valve driver to actuate the valve todeliver bioactive agent from the agent reservoir to the agent outlet;the system further having a spring (or other source of stored mechanicalenergy) extending between the agent reservoir piston and a surface ofthe reusable part or of the disposable part to pressurize the agentreservoir when the spring is compressed and the agent reservoir containsa quantity of bioactive agent. The valve may be a rotatable valve havinga range of motion between 60° to 90°, inclusive. In some embodiments,the bolus chamber is configured to provide a bioactive agent dissolvedin a solvent to the agent outlet. The system may also have adisengagement button configured to disengage the reusable part from thedisposable part.

In some embodiments, the system may also have a transdermal patch (e.g.,a polypropylene membrane, optionally having pores with an average porediameter of about 0.02 μm to about 0.10 μm) communicating with theoutlet and adapted to transdermally deliver the bioactive agent to auser. In addition, some embodiments of the invention may include asolvent recovery chamber disposed in the disposable part andcommunicating with the transdermal patch, the solvent recovery chamberbeing adapted to receive gaseous phase solvent from the transdermalpatch. Such embodiments of the system may also have a desiccant orabsorbent material disposed in the solvent recovery chamber.

In some embodiments, the spring may be disposed in the disposable partprior to connecting the disposable part to the reusable part, and insome embodiments the spring may be disposed in the reusable part priorto connecting the disposable part to the reusable part. Some embodimentsmay have a second spring extending between the bolus chamber piston anda surface, the second spring being at least partially loaded when aquantity of bioactive agent is present in the bolus chamber. In someembodiments, the second spring extends between the bolus chamber pistonand a surface in the disposable part, the bolus chamber piston beingadapted to move and load the second spring when pressurized bioactiveagent enters the bolus chamber from the agent reservoir through thevalve. In other embodiments, the second spring extends between the boluschamber piston and a surface in the reusable part.

In embodiments employing a transdermal patch, the system may also have avapor permeable membrane in the disposable part adjacent to thetransdermal patch. In such embodiments, the agent outlet may beconfigured to provide the bioactive agent dissolved in the solvent to aspace between the transdermal patch and the vapor permeable membrane.The vapor permeable membrane may also be in fluid communication with thesolvent recovery chamber. The transdermal patch may be adapted to allowthe bioactive agent to pass through a plurality of openings in thetransdermal patch while substantially preventing the solvent frompassing through the plurality of openings of the transdermal patch.

In some embodiments, the agent reservoir and bolus chamber areconfigured to contain a bioactive agent and a solvent solutioncomprising alcohol and water, wherein the solvent solution has a ratioof water to alcohol of about 40:60 to about 60:40.

Some embodiments of the system may include a connection indicatoroperatively connected to the control electronics to provide anindication that the reusable part has been connected to the disposablepart. The connection indicator may be, e.g., a movable switch and/or twomembers that cooperate to close a circuit, such as a first conductor(formed, e.g., of a conductive elastomeric material) on the reusablepart and a second conductor (formed, e.g., of a conductive elastomericmaterial) on the disposable part, the first and second conductors beingarranged and disposed to close an electric circuit when the reusablepart is connected to the disposable part.

Some embodiments of the system may include a display on the reusablepart, the display being operatively connected to the controlelectronics. The system may also include one or more user actuatablebuttons operatively connected to the control electronics, the controlelectronics may also be further adapted to detect actuation of a buttonand to display a message on the display in response to detectingactuation of the button. The system may also have a wireless transmitterconfigured to wirelessly transmit to another device a signal indicatingactuation of the button and may also have a receiver configured toreceive a wireless signal from the other device, the control electronicsbeing further configured to display a message on the display in responseto the wireless signal received on the receiver.

In some embodiments, the system includes a wireless data communicationmodule configured to send and receive data wirelessly to a network or acomputing device via, e.g., a Bluetooth connection. In some embodiments,the system has one or more buttons configured to provide an input to thesystem, such as, e.g., to change the system operation mode and/or selectinputs.

In some embodiments, the bioactive agent is selected from the groupconsisting of: Acamprosate, Acetaminophen, Acetaminophen+Oxycodone,Alevicyn SG, Alfentanil, Allopurinol, Almotriptan, Alprazolam,Alprazolam XR, Amitriptylinem, Amoxapine, Apomorphine, Aripiprazole,Armodafinil, Asenapine maleate, Atomoxetine, Azelastine HCL, Baclofen,Benzbromarone, Benzydamine, Brexpiprazole, Budesonide, Bupivacaine,Buprenorphine, Buprenorphine+Nalaxone, Bupropion, BupropionHydrobromide, Bupropion Hydrochloride, Bupropion SR, Bupropion XR,Buspirone, Cabergoline, Capsaicin, Carbamazepine CR, Carbamazepine XR,Carbidopa+Levodopa Er, Carisprodol, Celecoxib, Citalopram, Clobazam,Clonazepam, Clonidine Patch, Clonidine SR, Clopidogrel, Colchicine,Cyclobenzaprine ER, Cyclobenzaprine PO, Dalteparin sodium,Desvenlafaxine, Desvenlafaxine ER, Dexamfetamine, DexmethylphenidateHcl, Dexmethylphenidate Hcl LA, Diazepam, Diclofenacm, Diclofenac Gel,Diclofenac IR, Diclofenac IV, Diclofenac Potassium IR, DiclofenacPotassium XR, Diclofenac Transdermal, Disulfiram, Divalproex Sodium,Dolasetron Mesilate, Doxepin, Dronabinol, Droxidopa, Duloxetine,Eletriptan, Entacapone, Escitalopram oxalate, Eslicarbazepine Acetate,Esomeprazole/naproxen, Estradiol, Estrogen, Eszopiclone, Ethosuximide,Etodolac, Ezogabine, Febuxostat, Felbamate, Fenbufen, Fentanyl Citrate,Fentanyl Oral, Fentanyl Patch, Fentanyl SL, Flunisolide, Fluorouracil,Fluoxetine, Fluticasone propionate, Fluvoxamine Cr, Formoterol,Fosphenytoin, Frovatriptan, Gabapentin, Gabapentin ER, Granisetron ER,Guanfacine, Hydrocodone Bitartrate CR, Hydrocodone+Acetaminophen,hydrocortisone, Hydromorphone Hcl, Hydroxyzine, Hypericum Extract,Ibuprofen, Indometacin, Ketorolac, Lacosamide, Lamotrigine, LamotrigineCDT, Lamotrigine ODT, Lamotrigine XR, Levetiracetam, Levetiracetam IR,Levetiracetam XR, Levomilnacipran, Levo salbutamol, Lidocaine Patch,Lidocaine/Tetracaine, Lisdexamfetamine, Lithium Carbonate, Lorazepam,Lorcaserin, Hydrochloride, Losartan, Loxapine, Meclizine, Meloxicam,Metaxalone, Methylphenidate, Methylphenidate Hydrochloride,Methylphenidate LA, Methylphenidate MR, Methylphenidate Patch,Milnacipran, Mirtazapine, Modafinil, Morphine, Morphine CR, Morphine ER,Nabilone, Nadolol, Naltrexone, Naproxen, Naratriptan, Nedocromil,Nefazodone, Nitroglycerin, Nitroglycerin Ointment, Olanzapine,Olanzapine IM, Olanzapine LA, Ondansetron, Ondansetron ODFS, OndansetronODT, Orlistat, Oxaprozin, Oxcarbazepine, Oxcarbazepine ER, Oxybutynin,Oxybutynin Gel, Oxycodone, Oxycodone+Acetominophen, OxycodoneHydrochloride, Oxycodone IR, Oxymorphone, Oxymorphone ER, Palonosetro,Pamidronate, Paroxetine, Paroxetine Mesylate, Perampanel,Phentermine+Topiramate, Phentermine Hydrochloride, PhentolamineMesylate, Pramipexole, Pramipexole-Er, Prasugrel, Prazepam, Prednisone,Pregabalin, Promethazine, Propofol, Quetiapine, Quetiapine Fumarate,Quetiapine Fumarate XR, Ramelteon, Rasagiline Mesylate, Remifentanil,Risperidone, Rivastigmine Tartrate, Rizatriptan, Ropinirole, RopiniroleXL, Ropivacaine, Rotigotine, Rufinamide, Salbutamol, Scopolamine,Selegiline, Selegiline ODT, Selegiline Transdermal, Sertraline, SodiumOxybate, Strontium, Sufentanil-Ent, Sumatriptan Autoinjector,Sumatriptan Needle-free, Sumatriptan Succinate, Suvorexant, Tapentadol,Tapentadol ER, Tasimelteon, Temazepam, Testosterone,Tetracaine+Lidocaine, Theophylline, Tiagabine, Tiotropium, TirofibanHcL, Tolcapone, Topiramate, Topiramate XR, Tramadol,Tramadol+Acetaminophen, Tramadol ER, Trazodone Cr, Triazolam,Trimipramine Maleate, Valproate Semisodium ER, Valproate Sodium,Venlafaxine, Venlafaxine ER, Vigabatrin, Vilazodone, Vortioxetine,Zaleplon, Zileuton, Ziprasidone, Zolmitriptan Oral, Zolmitriptan ZMT,Zolpidem, Zolpidem Spray, Zolpidem Tartrate CR, Zolpidem Tartrate Lowdose SL, Zolpidem Tartrate SL, norethisterone acetate (NETA), enapril,ethinyl estradiol, insulin, memantine, methamphetamine, norelgestromine,pergolide, Ramipril, tecrine, timolol, tolterodine and Zonisamide.

Another aspect of the invention provides a method for delivering abioactive agent with a two-part transdermal bioactive agent deliverysystem. In some embodiments, the method includes the steps of:connecting a reusable part of a delivery system to a disposable part ofthe delivery system; during the connecting step, compressing a spring(or other source of stored mechanical energy) extending from an agentreservoir of the disposable part to pressurize bioactive agent withinthe agent reservoir; actuating a valve driver in the reusable part tomove a valve in the disposable part to a first position to transferbioactive agent from the agent reservoir to a bolus chamber; andactuating the valve driver to move the valve to a second position totransfer bioactive agent from the bolus chamber to an agent outlet.

In embodiments in which the disposable part has a transdermal patchcommunicating with the agent outlet, the method includes the step oftransferring bioactive agent from the bolus chamber to the transdermalpatch. In some such embodiments in which the disposable part also has asolvent recovery chamber and the bioactive agent is dissolved in asolvent, the method may also include the step of receiving gaseous phasesolvent from the from the transdermal patch in the solvent recoverychamber. In some such embodiments in which the disposable part also hasa vapor permeable membrane, the receiving step may include the step ofpassing gaseous phase solvent through the vapor permeable membrane intothe solvent recovery chamber. In some embodiments, the transdermal patchmay include a polypropylene membrane with a plurality of pores having anaverage pore diameter of about 0.02 μm to about 0.10 μm, and thebioactive agent may be dissolved in a solution comprising alcohol andwater in a ratio of alcohol to water of about 40:60 to about 60:40.

Some embodiments include the step of compressing a second springextending from the bolus chamber to pressurize bioactive agent withinthe bolus chamber. In embodiments in which the system includes a pistonmovably disposed in the bolus chamber, the method may also include thestep of moving the piston with the second spring to move bioactive agentfrom the bolus chamber to the agent outlet. In some embodiments, thesecond spring may be compressed during the connecting step. In someembodiments, the second spring may be compressed when bioactive agent istransferred from the agent reservoir into the bolus chamber.

In some embodiments, the valve rotates between 60° to 90°, inclusive,during the actuating steps. In embodiments in which the system has apiston disposed in the agent reservoir, the method may include the stepof moving the piston with the spring to move bioactive agent from theagent reservoir to the bolus chamber.

In some embodiments, the method includes the step of, during or afterthe connecting step, providing an indication to a remote device that thedisposable part has been connected to the reusable part, such as bywirelessly transmitting connection information to the remote device.Some embodiments also include the step of activating a switch during theconnecting step to indicate that the disposable part has been connectedto the reusable part. Some embodiments also include the step of closinga circuit during the connecting step by contacting a conductive elementof the reusable part with a conductive element of the disposable part.At least one of the conductive elements may be a conductive elastomer.

Some embodiments include the step of programming delivery of thebioactive agent by actuating an input element on the reusable part. Someembodiments include the step of generating an indication that thedisposable part needs to be replaced. In some such embodiments, thegenerating step includes the step of monitoring time elapsed afterconnecting the disposable part to the reusable part and providing theindication that the disposable part needs to be replaced after apredetermined time. Some embodiments include the step of sendinginformation about operation of the delivery system from the reusablepart to a remote device.

In some embodiments, the method includes the step of receiving an inputfrom the user on the reusable part indicating that the user isexperiencing a craving. In some such embodiments, the method alsoincludes the step of wirelessly transmitting an indication of the inputto a remote device. The method may also include the step of receiving awireless signal indicating a psychological support in response to theinput from the user indicating the craving. The psychological supportmay be displayed, e.g., on a display of the reusable part and/or on theremote device.

In any embodiments of the method, the bioactive agent may be selectedfrom the group consisting of: Acamprosate, Acetaminophen,Acetaminophen+Oxycodone, Alevicyn SG, Alfentanil, Allopurinol,Almotriptan, Alprazolam, Alprazolam XR, Amitriptylinem, Amoxapine,Apomorphine, Aripiprazole, Armodafinil, Asenapine maleate, Atomoxetine,Azelastine HCL, Baclofen, Benzbromarone, Benzydamine, Brexpiprazole,Budesonide, Bupivacaine, Buprenorphine, Buprenorphine+Nalaxone,Bupropion, Bupropion Hydrobromide, Bupropion Hydrochloride, BupropionSR, Bupropion XR, Buspirone, Cabergoline, Capsaicin, Carbamazepine CR,Carbamazepine XR, Carbidopa+Levodopa Er, Carisprodol, Celecoxib,Citalopram, Clobazam, Clonazepam, Clonidine Patch, Clonidine SR,Clopidogrel, Colchicine, Cyclobenzaprine ER, Cyclobenzaprine PO,Dalteparin sodium, Desvenlafaxine, Desvenlafaxine ER, Dexamfetamine,Dexmethylphenidate Hcl, Dexmethylphenidate Hcl LA, Diazepam,Diclofenacm, Diclofenac Gel, Diclofenac IR, Diclofenac IV, DiclofenacPotassium IR, Diclofenac Potassium XR, Diclofenac Transdermal,Disulfiram, Divalproex Sodium, Dolasetron Mesilate, Doxepin, Dronabinol,Droxidopa, Duloxetine, Eletriptan, Entacapone, Escitalopram oxalate,Eslicarbazepine Acetate, Esomeprazole/naproxen, Estradiol, Estrogen,Eszopiclone, Ethosuximide, Etodolac, Ezogabine, Febuxostat, Felbamate,Fenbufen, Fentanyl Citrate, Fentanyl Oral, Fentanyl Patch, Fentanyl SL,Flunisolide, Fluorouracil, Fluoxetine, Fluticasone propionate,Fluvoxamine Cr, Formoterol, Fosphenytoin, Frovatriptan, Gabapentin,Gabapentin ER, Granisetron ER, Guanfacine, Hydrocodone Bitartrate CR,Hydrocodone+Acetaminophen, hydrocortisone, Hydromorphone Hcl,Hydroxyzine, Hypericum Extract, Ibuprofen, Indometacin, Ketorolac,Lacosamide, Lamotrigine, Lamotrigine CDT, Lamotrigine ODT, LamotrigineXR, Levetiracetam, Levetiracetam IR, Levetiracetam XR, Levomilnacipran,Levo salbutamol, Lidocaine Patch, Lidocaine/Tetracaine,Lisdexamfetamine, Lithium Carbonate, Lorazepam, Lorcaserin,Hydrochloride, Losartan, Loxapine, Meclizine, Meloxicam, Metaxalone,Methylphenidate, Methylphenidate Hydrochloride, Methylphenidate LA,Methylphenidate MR, Methylphenidate Patch, Milnacipran, Mirtazapine,Modafinil, Morphine, Morphine CR, Morphine ER, Nabilone, Nadolol,Naltrexone, Naproxen, Naratriptan, Nedocromil, Nefazodone,Nitroglycerin, Nitroglycerin Ointment, Olanzapine, Olanzapine IM,Olanzapine LA, Ondansetron, Ondansetron ODFS, Ondansetron ODT, Orlistat,Oxaprozin, Oxcarbazepine, Oxcarbazepine ER, Oxybutynin, Oxybutynin Gel,Oxycodone, Oxycodone+Acetominophen, Oxycodone Hydrochloride, OxycodoneIR, Oxymorphone, Oxymorphone ER, Palonosetro, Pamidronate, Paroxetine,Paroxetine Mesylate, Perampanel, Phentermine+Topiramate, PhentermineHydrochloride, Phentolamine Mesylate, Pramipexole, Pramipexole-Er,Prasugrel, Prazepam, Prednisone, Pregabalin, Promethazine, Propofol,Quetiapine, Quetiapine Fumarate, Quetiapine Fumarate XR, Ramelteon,Rasagiline Mesylate, Remifentanil, Risperidone, Rivastigmine Tartrate,Rizatriptan, Ropinirole, Ropinirole XL, Ropivacaine, Rotigotine,Rufinamide, Salbutamol, Scopolamine, Selegiline, Selegiline ODT,Selegiline Transdermal, Sertraline, Sodium Oxybate, Strontium,Sufentanil-Ent, Sumatriptan Autoinjector, Sumatriptan Needle-free,Sumatriptan Succinate, Suvorexant, Tapentadol, Tapentadol ER,Tasimelteon, Temazepam, Testosterone, Tetracaine+Lidocaine,Theophylline, Tiagabine, Tiotropium, Tirofiban HcL, Tolcapone,Topiramate, Topiramate XR, Tramadol, Tramadol+Acetaminophen, TramadolER, Trazodone Cr, Triazolam, Trimipramine Maleate, Valproate SemisodiumER, Valproate Sodium, Venlafaxine, Venlafaxine ER, Vigabatrin,Vilazodone, Vortioxetine, Zaleplon, Zileuton, Ziprasidone, ZolmitriptanOral, Zolmitriptan ZMT, Zolpidem, Zolpidem Spray, Zolpidem Tartrate CR,Zolpidem Tartrate Low dose SL, Zolpidem Tartrate SL, norethisteroneacetate (NETA), enapril, ethinyl estradiol, insulin, memantine,methamphetamine, norelgestromine, pergolide, Ramipril, tecrine, timolol,tolterodine and Zonisamide.

Yet another aspect of the invention provides a bioactive agent deliverysystem having an agent reservoir containing a bioactive agent and asolvent solution of alcohol and water, wherein the solvent solution hasa ratio of water to alcohol of about 40:60 to about 60:40; a membranecomprising polypropylene having a plurality of pores configured tocontact a skin of the wearer of the bioactive agent delivery system; avapor permeable membrane configured to allow vapor phase water andalcohol to pass through the vapor permeable membrane, the vaporpermeable membrane in fluid communication with the membrane; and adelivery conduit extending from the agent reservoir and in fluidcommunication with the membrane, the delivery conduit configured toprovide a dose of the bioactive agent and solvent solution from theagent reservoir to the membrane. In some embodiments, the membraneincludes polypropylene having an average pore diameter of about 0.02 μmto about 0.10 μm.

Another aspect of the invention provides a bioactive agent deliverysystem including: an agent reservoir containing a bioactive agent andsolvent solution; a membrane including polypropylene having a pluralityof pores configured to contact a skin of the wearer of the bioactiveagent delivery system, the plurality of pores having an average porediameter of about 0.02 μm to about 0.10 μm; a vapor permeable membraneconfigured to allow vapor phase solvent solution to pass through thevapor permeable membrane, the vapor permeable membrane in fluidcommunication with the membrane; and a delivery conduit extending fromthe agent reservoir and in fluid communication with the membrane, thedelivery conduit configured to provide a dose of the bioactive agent andsolvent solution from the agent reservoir to the membrane. The solventsolution may include alcohol and water in a ratio of water to alcohol ofabout 40:60 to about 60:40.

Another aspect of the invention provides a bioactive agent deliverysystem including: an agent reservoir containing a bioactive agent andsolvent solution including alcohol and water in a ratio of water toalcohol of about 40:60 to about 60:40; a membrane (such as, e.g., atransdermal membrane) including polypropylene having a plurality ofpores configured to contact a skin of the wearer of the bioactive agentdelivery system; a vapor permeable membrane configured to allow vaporphase water and alcohol to pass through the vapor permeable membrane,the vapor permeable membrane in fluid communication with the membrane; adelivery conduit extending from the agent reservoir and in fluidcommunication with the membrane, the delivery conduit configured toprovide a dose of the bioactive agent and solvent solution from theagent reservoir to the membrane; and a control unit configured tocontrol the bioactive agent delivery system to provide a dose of thebioactive agent and solvent solution from the agent reservoir to themembrane, the control unit further configured to provide abio-synchronous drug delivery protocol to the wearer of the bioactiveagent delivery system.

In some embodiments, the control unit is further configured to record atime of administration of the bioactive agent, a dosage amount of thebioactive agent, and a time at which dosing ceased. In some embodimentsthe bioactive agent delivery system may also include a wireless datatransfer unit configured to wirelessly transmit the time ofadministration of the bioactive agent, the dosage amount of thebioactive agent, and the time at which dosing ceased to a remote networkor device. In some embodiments, the bioactive agent delivery system mayalso include a sensor configured to determine when the agent reservoiris connected to the bioactive agent delivery system. In someembodiments, the control unit is configured to gather wearer data duringthe bio-synchronous drug delivery protocol and provide a psychologicalsupport based on the patient data.

In some embodiments, the solvent solution has a ratio of water toalcohol of about 45:55 to about 55:45; about 46:54 to about 54:46; about47:53 to about 53:47; about 48:52 to about 52:48; or about 49:51 toabout 51:49. In some embodiments, the solvent solution includes one ormore of a: surfactant, excipient, or other component intended to enhancepermeation or decrease skin sensitivity or skin reaction.

In some embodiments, the system also includes a disposable partcomprising the agent reservoir, the agent reservoir having a pistonmovably disposed therein, a bolus chamber, the bolus chamber having apiston movably disposed therein, the volume of the bolus chamber beingless than the volume of the agent reservoir, and a valve having a firstposition communicating the agent reservoir with the bolus chamber and asecond position communicating the bolus chamber with the deliveryconduit; and a reusable part including a valve driver, a power sourceand control electronics, the control electronics being adapted tocontrol the valve driver to actuate the valve to deliver bioactive agentfrom the agent reservoir to the delivery conduit.

In some embodiments, the plurality of pores of the membrane have anon-circular cross section. In some embodiments, the plurality of poresof the membrane include longitudinal slits having a longitudinal crosssection. In some embodiments, the membrane includes a surface areaconfigured to contact the skin and the plurality of pores have an opensurface area of about 25% to about 75% of the surface area of themembrane; about 35% to about 45% of the surface area of the membrane; orabout 40% to about 42% of the surface area of the membrane.

In some embodiments, the alcohol is selected from the group consistingof: isopropanol, ethanol, and methanol.

Some embodiments of the system also include a solvent recovery chambercommunicating with the membrane, the solvent recovery chamber beingadapted to receive vapor phase solvent solution from the membrane. Someembodiments include a desiccant or an absorbent material disposed in thesolvent recovery chamber. The vapor permeable membrane may have anaverage pore size of less than about 10 microns, and the pores mayprovide an open surface area of about 50% or less than the surface areaof the vapor permeable membrane.

In some embodiments, the delivery conduit is configured to provide thedose of the bioactive agent and solvent solution to a space between themembrane and the vapor permeable membrane. In some embodiments, thedelivery conduit is configured to provide the dose of the bioactiveagent and solvent solution to a substantially centrally located sectionof the membrane, and in other embodiments, the delivery conduit isconfigured to provide the dose of the bioactive agent and solventsolution to an off-center section of the membrane.

In some embodiments, the membrane has a surface area that is less thanabout 15 cm², less than about 10 cm², or from about 15 cm² to about 30cm².

In some embodiments, the delivery conduit is configured to move the doseof the bioactive agent and solvent solution from a first reservoir tothe agent reservoir. The agent reservoir may have a volume of about 5microliters to about 3 milliliters, or less than about 250 μL.

Some embodiments of the system include a delivery controller. In somesuch embodiments, the membrane has a surface area and the deliverycontroller and delivery conduit are configured to provide the dose witha volume of less than about 250 μL per 10 cm2 of surface area of themembrane. In some such embodiments, the delivery controller and deliveryconduit are configured to provide the dose with a volume of betweenabout 75 μL to about 250 μL per 10 cm² of surface area of the membrane.In some such embodiments, the delivery controller and delivery conduitare configured to provide the dose with a volume of less than about 150μL per 10 cm² of surface area of the membrane.

In some embodiments, the bioactive agent includes nicotine. Theconcentration of nicotine in the solvent solution may be from about 0.5%to about 20% by volume.

In some embodiments, the system has a removable portion including theagent reservoir comprising the bioactive agent and the solvent solution.The removable portion may further include a bioactive agent sourcereservoir configured to provide the bioactive agent and solvent solutionto the agent reservoir. In some embodiments, the bioactive agent sourcereservoir may have a volume of less than about 3 nil. Some embodimentsof the system also include a sensor configured to determine when theremovable portion is connected to the bioactive agent delivery system.

In some embodiments, the system also includes a control unit configuredto control the bioactive agent delivery system to provide a dose of thebioactive agent and solvent solution from the agent reservoir to themembrane, the control unit further configured to provide abio-synchronous drug delivery protocol to the wearer of the bioactiveagent delivery system. The control unit may be further configured torecord a time of administration of the bioactive agent, a dosage amountof the bioactive agent, and a time at which dosing ceased. In someembodiments, the system also includes a wireless data transfer unitconfigured to wirelessly transmit the time of administration of thebioactive agent, the dosage amount of the bioactive agent, and the timeat which dosing ceased to a remote network or device. The control unitmay also be configured to gather wearer data during the bio-synchronousdrug delivery protocol and provide a psychological support based on thepatient data.

In these embodiments, the bioactive agent delivery the bioactive agentmay be selected from the group consisting of: Acamprosate,Acetaminophen, Acetaminophen+Oxycodone, Alevicyn SG, Alfentanil,Allopurinol, Almotriptan, Alprazolam, Alprazolam XR, Amitriptylinem,Amoxapine, Apomorphine, Aripiprazole, Armodafinil, Asenapine maleate,Atomoxetine, Azelastine HCL, Baclofen, Benzbromarone, Benzydamine,Brexpiprazole, Budesonide, Bupivacaine, Buprenorphine,Buprenorphine+Nalaxone, Bupropion, Bupropion Hydrobromide, BupropionHydrochloride, Bupropion SR, Bupropion XR, Buspirone, Cabergoline,Capsaicin, Carbamazepine CR, Carbamazepine XR, Carbidopa+Levodopa Er,Carisprodol, Celecoxib, Citalopram, Clobazam, Clonazepam, ClonidinePatch, Clonidine SR, Clopidogrel, Colchicine, Cyclobenzaprine ER,Cyclobenzaprine PO, Dalteparin sodium, Desvenlafaxine, DesvenlafaxineER, Dexamfetamine, Dexmethylphenidate Hcl, Dexmethylphenidate Hcl LA,Diazepam, Diclofenacm, Diclofenac Gel, Diclofenac IR, Diclofenac IV,Diclofenac Potassium IR, Diclofenac Potassium XR, DiclofenacTransdermal, Disulfiram, Divalproex Sodium, Dolasetron Mesilate,Doxepin, Dronabinol, Droxidopa, Duloxetine, Eletriptan, Entacapone,Escitalopram oxalate, Eslicarbazepine Acetate, Esomeprazole/naproxen,Estradiol, Estrogen, Eszopiclone, Ethosuximide, Etodolac, Ezogabine,Febuxostat, Felbamate, Fenbufen, Fentanyl Citrate, Fentanyl Oral,Fentanyl Patch, Fentanyl SL, Flunisolide, Fluorouracil, Fluoxetine,Fluticasone propionate, Fluvoxamine Cr, Formoterol, Fosphenytoin,Frovatriptan, Gabapentin, Gabapentin ER, Granisetron ER, Guanfacine,Hydrocodone Bitartrate CR, Hydrocodone+Acetaminophen, hydrocortisone,Hydromorphone Hcl, Hydroxyzine, Hypericum Extract, Ibuprofen,Indometacin, Ketorolac, Lacosamide, Lamotrigine, Lamotrigine CDT,Lamotrigine ODT, Lamotrigine XR, Levetiracetam, Levetiracetam IR,Levetiracetam XR, Levomilnacipran, Levo salbutamol, Lidocaine Patch,Lidocaine/Tetracaine, Lisdexamfetamine, Lithium Carbonate, Lorazepam,Lorcaserin, Hydrochloride, Losartan, Loxapine, Meclizine, Meloxicam,Metaxalone, Methylphenidate, Methylphenidate Hydrochloride,Methylphenidate LA, Methylphenidate MR, Methylphenidate Patch,Milnacipran, Mirtazapine, Modafinil, Morphine, Morphine CR, Morphine ER,Nabilone, Nadolol, Naltrexone, Naproxen, Naratriptan, Nedocromil,Nefazodone, Nitroglycerin, Nitroglycerin Ointment, Olanzapine,Olanzapine IM, Olanzapine LA, Ondansetron, Ondansetron ODFS, OndansetronODT, Orlistat, Oxaprozin, Oxcarbazepine, Oxcarbazepine ER, Oxybutynin,Oxybutynin Gel, Oxycodone, Oxycodone+Acetaminophen, OxycodoneHydrochloride, Oxycodone IR, Oxymorphone, Oxymorphone ER, Palonosetro,Pamidronate, Paroxetine, Paroxetine Mesylate, Perampanel,Phentermine+Topiramate, Phentermine Hydrochloride, PhentolamineMesylate, Pramipexole, Pramipexole-Er, Prasugrel, Prazepam, Prednisone,Pregabalin, Promethazine, Propofol, Quetiapine, Quetiapine Fumarate,Quetiapine Fumarate XR, Ramelteon, Rasagiline Mesylate, Remifentanil,Risperidone, Rivastigmine Tartrate, Rizatriptan, Ropinirole, RopiniroleXL, Ropivacaine, Rotigotine, Rufinamide, Salbutamol, Scopolamine,Selegiline, Selegiline ODT, Selegiline Transdermal, Sertraline, SodiumOxybate, Strontium, Sufentanil-Ent, Sumatriptan Autoinjector,Sumatriptan Needle-free, Sumatriptan Succinate, Suvorexant, Tapentadol,Tapentadol ER, Tasimelteon, Temazepam, Testosterone,Tetracaine+Lidocaine, Theophylline, Tiagabine, Tiotropium, TirofibanHcL, Tolcapone, Topiramate, Topiramate XR, Tramadol,Tramadol+Acetaminophen, Tramadol ER, Trazodone Cr, Triazolam,Trimipramine Maleate, Valproate Semisodium ER, Valproate Sodium,Venlafaxine, Venlafaxine ER, Vigabatrin, Vilazodone, Vortioxetine,Zaleplon, Zileuton, Ziprasidone, Zolmitriptan Oral, Zolmitriptan ZMT,Zolpidem, Zolpidem Spray, Zolpidem Tartrate CR, Zolpidem Tartrate Lowdose SL, Zolpidem Tartrate SL, norethisterone acetate (NETA), enapril,ethinyl estradiol, insulin, memantine, methamphetamine, norelgestromine,pergolide, Ramipril, tecrine, timolol, tolterodine and Zonisamide.

Another aspect of the invention provides a method for providing abioactive agent. In some embodiments the method includes the followingsteps: moving a bioactive agent in a solvent solution comprising alcoholand water from an agent reservoir of a drug delivery device into contactwith a membrane of the drug delivery device, wherein the solventsolution has a ratio of water to alcohol of about 40:60 to about 60:40,the drug delivery device in contact with a skin of the wearer, themembrane comprising polypropylene having a plurality of pores configuredto contact the skin of the wearer; passing bioactive agent through theplurality of pores of the membrane into contact with the skin of thewearer; and passing vapor phase solvent solution through a vaporpermeable membrane of the drug delivery device while preventing liquidphase solvent solution from passing through the vapor permeablemembrane.

In some embodiments, the step of passing vapor phase solvent solutionincludes the step of passing vapor phase solvent solution through thevapor permeable membrane into a solvent recovery chamber of the drugdelivery device. The method may also include the step of collecting thesolvent solution with a desiccant and/or absorbent material disposed inthe solvent recovery chamber.

In some embodiments, the step of moving the bioactive agent in thesolvent solution includes providing the dose of the bioactive agent andsolvent solution to a space between the membrane and the vapor permeablemembrane. The dose of the bioactive agent and solvent solution may beprovided to a substantially centrally located section of the membrane orto an off-center section of the membrane. In some embodiments, dose ofthe bioactive agent and solvent solution is provided through multipleorifices onto the membrane. In some embodiments, the membrane has asurface area that is less than about 15 cm², between about 15 cm² and 30cm², or less than about 10 cm².

In some embodiments, the method includes the step of moving the dose ofthe bioactive agent and solvent solution from a first reservoir of thedrug delivery device to the agent reservoir. In some embodiments, thedose has a volume of less than about 250 μL, per 10 cm² of surface areaof the membrane, between about 75 μL to about 250 μL, per 10 cm² ofsurface area of the membrane, or less than about 150 μL, per 10 cm² ofsurface area of the membrane. In some embodiments, the membrane has anaverage pore diameter of about 0.02 μm to about 0.10 μm, and passingbioactive agent includes passing bioactive agent through the pluralityof pores having the average pore diameter of about 0.02 μm to about 0.10μm

In some embodiments, the solvent solution has a ratio of water toalcohol of about 45:55 to about 55:45, about 46:54 to about 54:46, about47:53 to about 53:47, about 48:52 to about 52:48, or about 49:51 toabout 51:49.

In some embodiments, the membrane includes a surface area configured tocontact the skin and the plurality of pores have an open surface area ofabout 35% to about 65% of the surface area of the membrane, about 35% toabout 45% of the surface area of the membrane, or about 40% to about 42%of the surface area of the membrane.

In some embodiments, the alcohol is selected from the group consistingof: isopropanol, ethanol, and methanol. In some embodiments, the agentreservoir has a volume of less than about 3 ml or less than about 250μL.

Some embodiments include the step of moving the bioactive agent in thesolvent solution from the agent reservoir into contact with the membraneand passing bioactive agent through the plurality of pores of themembrane into contact with the skin of the wearer to provide abio-synchronous drug delivery protocol to the wearer.

Some embodiments include the step of gathering patient data of thewearer, such as patient emotional state data, e.g., cravings. The methodmay also include the step of providing a psychological support based onthe patient data.

Some embodiments include the step of analyzing wearer compliance by oneor more of determining whether the drug delivery device was removed, atreatment in a drug delivery protocol was missed, or if the drugdelivery protocol was interrupted.

Some embodiments include the step of treating ulcerative colitis orParkinson's disease by providing the bioactive agent to the wearer. Inany of the embodiments, the bioactive agent may be selected from thegroup consisting of: nicotine, Acamprosate, Acetaminophen,Acetaminophen+Oxycodone, Alevicyn SG, Alfentanil, Allopurinol,Almotriptan, Alprazolam, Alprazolam XR, Amitriptylinem, Amoxapine,Apomorphine, Aripiprazole, Armodafinil, Asenapine maleate, Atomoxetine,Azelastine HCL, Baclofen, Benzbromarone, Benzydamine, Brexpiprazole,Budesonide, Bupivacaine, Buprenorphine, Buprenorphine+Nalaxone,Bupropion, Bupropion Hydrobromide, Bupropion Hydrochloride, BupropionSR, Bupropion XR, Buspirone, Cabergoline, Capsaicin, Carbamazepine CR,Carbamazepine XR, Carbidopa+Levodopa Er, Carisprodol, Celecoxib,Citalopram, Clobazam, Clonazepam, Clonidine Patch, Clonidine SR,Clopidogrel, Colchicine, Cyclobenzaprine ER, Cyclobenzaprine PO,Dalteparin sodium, Desvenlafaxine, Desvenlafaxine ER, Dexamfetamine,Dexmethylphenidate Hcl, Dexmethylphenidate Hcl LA, Diazepam,Diclofenacm, Diclofenac Gel, Diclofenac IR, Diclofenac IV, DiclofenacPotassium IR, Diclofenac Potassium XR, Diclofenac Transdermal,Disulfiram, Divalproex Sodium, Dolasetron Mesilate, Doxepin, Dronabinol,Droxidopa, Duloxetine, Eletriptan, Entacapone, Escitalopram oxalate,Eslicarbazepine Acetate, Esomeprazole/naproxen, Estradiol, Estrogen,Eszopiclone, Ethosuximide, Etodolac, Ezogabine, Febuxostat, Felbamate,Fenbufen, Fentanyl Citrate, Fentanyl Oral, Fentanyl Patch, Fentanyl SL,Flunisolide, Fluorouracil, Fluoxetine, Fluticasone propionate,Fluvoxamine Cr, Formoterol, Fosphenytoin, Frovatriptan, Gabapentin,Gabapentin ER, Granisetron ER, Guanfacine, Hydrocodone Bitartrate CR,Hydrocodone+Acetaminophen, hydrocortisone, Hydromorphone Hcl,Hydroxyzine, Hypericum Extract, Ibuprofen, Indometacin, Ketorolac,Lacosamide, Lamotrigine, Lamotrigine CDT, Lamotrigine ODT, LamotrigineXR, Levetiracetam, Levetiracetam IR, Levetiracetam XR, Levomilnacipran,Levo salbutamol, Lidocaine Patch, Lidocaine/Tetracaine,Lisdexamfetamine, Lithium Carbonate, Lorazepam, Lorcaserin,Hydrochloride, Losartan, Loxapine, Meclizine, Meloxicam, Metaxalone,Methylphenidate, Methylphenidate Hydrochloride, Methylphenidate LA,Methylphenidate MR, Methylphenidate Patch, Milnacipran, Mirtazapine,Modafinil, Morphine, Morphine CR, Morphine ER, Nabilone, Nadolol,Naltrexone, Naproxen, Naratriptan, Nedocromil, Nefazodone,Nitroglycerin, Nitroglycerin Ointment, Olanzapine, Olanzapine IM,Olanzapine LA, Ondansetron, Ondansetron ODFS, Ondansetron ODT, Orlistat,Oxaprozin, Oxcarbazepine, Oxcarbazepine ER, Oxybutynin, Oxybutynin Gel,Oxycodone, Oxycodone+Acetaminophen, Oxycodone Hydrochloride, OxycodoneIR, Oxymorphone, Oxymorphone ER, Palonosetro, Pamidronate, Paroxetine,Paroxetine Mesylate, Perampanel, Phentermine+Topiramate, PhentermineHydrochloride, Phentolamine Mesylate, Pramipexole, Pramipexole-Er,Prasugrel, Prazepam, Prednisone, Pregabalin, Promethazine, Propofol,Quetiapine, Quetiapine Fumarate, Quetiapine Fumarate XR, Ramelteon,Rasagiline Mesylate, Remifentanil, Risperidone, Rivastigmine Tartrate,Rizatriptan, Ropinirole, Ropinirole XL, Ropivacaine, Rotigotine,Rufinamide, Salbutamol, Scopolamine, Selegiline, Selegiline ODT,Selegiline Transdermal, Sertraline, Sodium Oxybate, Strontium,Sufentanil-Ent, Sumatriptan Autoinjector, Sumatriptan Needle-free,Sumatriptan Succinate, Suvorexant, Tapentadol, Tapentadol ER,Tasimelteon, Temazepam, Testosterone, Tetracaine+Lidocaine,Theophylline, Tiagabine, Tiotropium, Tirofiban HcL, Tolcapone,Topiramate, Topiramate XR, Tramadol, Tramadol+Acetaminophen, TramadolER, Trazodone Cr, Triazolam, Trimipramine Maleate, Valproate SemisodiumER, Valproate Sodium, Venlafaxine, Venlafaxine ER, Vigabatrin,Vilazodone, Vortioxetine, Zaleplon, Zileuton, Ziprasidone, ZolmitriptanOral, Zolmitriptan ZMT, Zolpidem, Zolpidem Spray, Zolpidem Tartrate CR,Zolpidem Tartrate Low dose SL, Zolpidem Tartrate SL, norethisteroneacetate (NETA), enapril, ethinyl estradiol, insulin, memantine,methamphetamine, norelgestromine, pergolide, Ramipril, tecrine, timolol,tolterodine and Zonisamide.

Still another aspect of the invention provides a method of using abioactive agent delivery device, including the following steps:receiving an input from a button on the bioactive agent delivery devicefrom a wearer of the device indicating a craving; transmitting a signalindicating the craving wirelessly over a network or to another device;and providing a supportive message to the wearer in response to thetransmitted signal. Some embodiments also include the step of providingthe supportive message by an e-mail, text message, or smartphonenotification. The method may also include the step of sending anotification of the craving to a remote device, such as that of asponsor or other contact provided by the wearer.

Some embodiments include the step of engaging a disposable part and areusable part of the bioactive agent delivery device. The method mayalso include the step of providing an indication that the disposablepart and the reusable part have been engaged and, optionally, wirelesslytransmitting a signal indicating engagement of the disposable part andthe reusable part a computer or other remote device using, e.g., aBluetooth protocol.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 is a block diagram of a two-part bioactive agent delivery systemaccording to one embodiment of the invention.

FIG. 2 is a block diagram of a two-part bioactive agent delivery systemaccording to another embodiment of the invention.

FIGS. 3A-3B show a schematic of part of the disposable portion of atwo-part bioactive agent delivery system.

FIG. 4A shows a block diagram of another two-part bioactive agentdelivery system using a motorized valve driver and a spring controllablebolus chamber.

FIG. 4B shows a block diagram of a two-part bioactive agent deliverysystem where the disposable portion has a transdermal patch and asolvent recovery mechanism.

FIGS. 5A and 5B are schematic views of portions of a two-part bioactiveagent with a spring controllable bolus chamber.

FIG. 6 shows a shape-memory valve driver that can be used in a two-partbioactive agent delivery system.

FIG. 7 shows a shape-memory valve driver part that can be used in atwo-part bioactive agent delivery system such as the system shown inFIG. 1.

FIG. 8 shows a motorized valve driver that can be used in a two-partbioactive agent delivery system.

FIGS. 9A-9E show an embodiment of a two-part bioactive agent deliverysystem according to the invention.

FIG. 10 is a perspective view of a two-part bioactive agent deliverysystem according to an embodiment of the invention.

FIGS. 11A-11C show different views of the reusable portion of thetwo-part bioactive agent delivery system of FIG. 10. FIG. 11A is aperspective view of the reusable portion.

FIG. 11B is a perspective view of the reusable portion with internalcomponents shown in phantom. FIG. 11C is a side sectional view of thereusable portion along the line C-C in FIG. 11B.

FIG. 12 is a sectional view of an embodiment of a disposable part andreusable part of a bioactive agent delivery system.

FIG. 13 is an exploded view showing aspects of a disposable part with atransdermal patch and solvent recovery mechanism for deliveringbioactive agent to a user.

FIGS. 14A-14D show aspects of a transdermal patch and a solvent recoverymechanism for use in a two-part bioactive agent delivery system, such asthat shown in FIG. 15. FIGS. 14A and 14C are exploded top perspectiveviews of the transdermal patch and a solvent recovery mechanism, andFIG. 14B is an exploded bottom perspective view of the transdermal patchand a solvent recovery mechanism. FIG. 14D illustrates assembly of thetransdermal patch and a solvent recovery mechanism.

FIGS. 15A-15E show an embodiment of a disposable portion for use with atwo-part bioactive agent delivery system. FIG. 15A is a plan view. FIG.15B is an exploded perspective view. FIGS. 15C-E are perspective viewsof the manifold of the disposable portion.

FIGS. 16A-16B show yet another embodiment of a disposable portion foruse with a two-part transdermal bioactive agent delivery system. FIG.16A is a plan view. FIG. 16B is an exploded perspective view.

FIGS. 17A-17E show another embodiment of a disposable portion for usewith a two-part transdermal bioactive agent delivery system. FIG. 17A isa plan view. FIG. 17B is an exploded perspective view. FIGS. 17C and 17Dare top and bottom views, respectively, of components of the disposableportion. FIG. 17E is an exploded perspective view of components of thedisposable portion.

FIGS. 18A-18C show yet another embodiment of a disposable portion foruse with a two-part transdermal bioactive agent delivery system. FIG.18A is a plan view. FIG. 18B is a sectional view. FIG. 18C is anexploded perspective view.

FIGS. 19A-19F show another embodiment of a disposable portion for usewith a two-part transdermal bioactive agent delivery system. FIG. 19A isa plan view. FIG. 19B is a plan view of a desiccant housing of thedisposable portion. FIG. 19C is an exploded perspective view. FIGS. 19Dand 19E are plan views of a structural support. FIG. 19F is an explodedperspective view of parts of the disposable portion.

FIGS. 20A-20E show different views of a yet another embodiment of atwo-part transdermal bioactive agent delivery system. FIG. 20A is aperspective view of the system.

FIGS. 20B and 20C are exploded perspective views of the two main partsof the system.

FIGS. 20D and 20E are sectional views of the reusable part of thesystem.

FIGS. 21A-21F show another embodiment of a two-part transdermalbioactive agent delivery system. FIG. 21A is a perspective view of thesystem. FIG. 21B is an exploded perspective view of the system. FIGS.21C and 21D show cutaway perspective views of the system. FIGS. 21E and21F show sectional views.

FIG. 22A shows an exploded perspective view of a valve core and valvedriver for rotating the core.

FIG. 22B shows a close-up view of the valve driver shown in FIG. 22A.

FIG. 22C shows an exploded cross-sectional view of the valve core andvalve driver shown in FIG. 22A.

FIG. 22D shows a perspective view of another valve driver that can beused with the valve core shown in FIGS. 22A and 22C.

FIG. 23 shows a partially transparent perspective view of a two-partbioactive agent delivery system with a mechanism for ejecting thedisposable part from the reusable part.

FIG. 24A shows a partially transparent perspective view of an embodimentof a bioactive agent delivery system with a reusable part and adisposable part with a second mechanism to prevent sudden release ofspring force.

FIG. 24B shows a partially transparent perspective view of anotherembodiment of a bioactive agent delivery system with a reusable part anda disposable part with a second mechanism to prevent sudden release ofspring force.

FIG. 25 is an exploded view showing yet another embodiment of abioactive agent delivery system with a reusable part and disposablepart.

FIG. 26A is an exploded perspective view of yet another embodiment of abioactive agent delivery system with a reusable part and a disposablepart.

FIG. 26B is a perspective view of the system of FIG. 26A.

FIG. 26C is an elevational view of the system of FIG. 26A.

FIGS. 27A and 27B are perspective views of the system of FIG. 26A.

FIGS. 27C and 27D are top elevational views of the system of FIG. 26A.

FIG. 28A-F are exploded perspective views of portions of the system ofFIG. 26A.

FIGS. 28A-C show details of a reusable part of the system. FIGS. 28D-Fshow details of a disposable part of the system.

FIG. 29 is a schematic drawing illustrating a connection feature of thesystem of FIG. 26A.

FIG. 30 is a photograph of various solvent and drug compositionsinteracting with a Celgard® 2400 membrane.

FIG. 31 is a photograph of various solvent and drug compositionsinteracting with a Celgard® 2500 membrane.

FIG. 32 is a photograph of various solvent and drug compositionsinteracting with a Celgard® 3501 membrane.

DETAILED DESCRIPTION

Described herein are systems, devices, and methods for delivery of adrug or other bioactive agent to a user in need. A bioactive agentdelivery system as described herein may be useful for delivering abioactive agent to a user for addiction or dependency management orprevention such as for a drug addiction, for diabetes or other diseasemanagement or prevention, for pain management or prevention or foranother therapeutic or prophylactic purpose. The systems, devices, andmethods may be especially useful for delivering multiple doses of a drugor other bioactive agent to a user over time with a safe, inexpensive,convenient, and easy-to-use system that minimizes risk of a drug orother bioactive agent overdose. A bioactive agent delivery system asdescribed herein may be configured to store multiple doses of abioactive agent and to deliver multiple doses (also referred to asboluses) of the bioactive agent to a user over time.

A bioactive agent delivery system may reproducibly deliver a fixedamount of a bioactive agent to a user, such as to a user's skin, to havea therapeutic or prophylactic effect on the user. In some variations, abioactive agent delivery system may be configured to be wearable and todeliver a fixed amount of a bioactive agent to a user's skin in arelatively thin, quiet, easy to use, convenient, electronicallycontrolled system. Such a bioactive agent delivery system may beconfigured to be attached to a user's body (such as for a day or shorteror longer), connect with a user's skin, and deliver a bioactive agentacross the user's skin.

The systems described herein can include a transdermal membrane thatcontacts the wearer's skin. A drug or other bioactive agent and solventsolution can be delivered in a controlled amount to the transdermalmembrane. The transdermal membrane can be configured to minimizepermeation of the solvent solution while permitting diffusion of thedrug or other bioactive agent across the membrane and into contact withthe skin. The solvent solution can be removed through a vapor permeablemembrane. The systems described herein can efficiently deliversubstantially all of the drug or other bioactive agent across thetransdermal membrane into contact with the wearer's skin.

The systems described herein can more efficiently deliver a drug orother bioactive agent versus prior art drug delivery systems, such aspatches. Patches deliver drugs or bioactive agents based on diffusionand typically have a large amount of residual drug left in the patchafter use. The residual drug left in the patch can present a high safetyrisk for children and animals. For example, children can accidentallythink that the patch is candy and chew or eat the patch. When a drug orbioactive agent that has a toxicity to small children is used then thepatches can present a poisoning hazard. The systems described hereindeliver substantially all of the drug or bioactive agent that isdelivered to the transdermal membrane. Thus, there is minimal poisoningrisk from residual drug left on the transdermal membrane. Any drug andsolvent remaining within the device, such as present in the drugreservoir(s) of the device is protected and difficult to access forchildren and animals.

In some embodiments, the transdermal membrane can be designed such thatthe drug or bioactive agent only diffuses when the transdermal membraneis in contact with skin. In some cases the drug or bioactive agent doesnot pass through the transdermal membrane unless the transdermalmembrane is in contact with a skin of the wearer.

The composition of the solvent can also be designed and selected tooptimize the diffusion of the drug or bioactive agent across thetransdermal membrane. The composition of the solvent can also be chosenin combination with the transdermal membrane to achieve the desired drugor bioactive agent delivery rate.

A bioactive agent delivery system according to this invention may be atwo-part system: a reusable part (also referred to as a durable part)and a disposable part (also called a replaceable or disposable part)that can be removably attached to the reusable part so that the reusablepart can control the disposable part. The disposable part may includebioactive agent and system parts that come into contact with bioactiveagent, and the reusable part may not contain bioactive agent or systemparts that come into contact with bioactive agent. In this way, areusable part can be used with a plurality of disposable parts over timethat can provide a fresh supply of bioactive agent to the user as neededto replace a bioactive agent supply that has been used up or expired,while reusing components that are still usable to save money andmaterials and minimize waste.

Bioactive agent delivery systems are disclosed herein. The systems caninclude an agent reservoir comprising a bioactive agent and a solventsolution, a membrane comprising polypropylene having a plurality ofpores configured to contact a skin of the wearer of the bioactive agentdelivery system, a vapor permeable membrane configured to allow vaporphase solvent solution to pass through the vapor permeable membrane, anda delivery conduit extending from the agent reservoir and in fluidcommunication with the membrane. The delivery conduit can be configuredto provide a dose of the bioactive agent and solvent solution from theagent reservoir to the membrane. The membrane contacting the skin can bea transdermal membrane.

In some embodiments a disposable part may include a solvent recoverymechanism, such as an absorbent or a desiccant, to remove solvent inwhich the bioactive agent is dissolved, and thus spent absorbent can bereadily replaced when a disposable part is replaced with new disposablepart containing fresh absorbent. Although a reusable part and adisposable part of a bioactive agent delivery system as described hereinare generally configured to work with each other, either may beadditionally or instead be used separately or as part of a differentsystem, such as with a different disposable part or with a differentreusable part.

A used disposable part may be readily removable from the reusable part,and a new disposable part attached to the reusable part for further useby a user. A disposable part may contain system parts that come intocontact with bioactive agent, such as a reservoir containing a pluralityof bioactive agent doses, a bolus chamber (also called a dosing chamber)for measuring a dose of bioactive agent from the reservoir and an outletfor delivering the bioactive agent from the bolus chamber to atransdermal patch or other user delivery component.

Bioactive delivery system embodiments may have more than two parts, ofcourse, without departing from the scope of the invention. Someembodiments may also integrate all device components into a single part.

A bioactive agent delivery system may be configured so that there is nodirect pathway from the reservoir to the outlet to minimize, or eveneliminate, risk of accidental bioactive agent delivery or overdose. Asindicated above, a system may be configured to provide multiple doses ofbioactive agent to a user (e.g., from a single disposable part), and thebioactive agent delivery system may include a valve configured toprevent a direct pathway between a reservoir containing a plurality ofbioactive doses and the user to minimize the risk of bioactive agentoverdose.

A bioactive agent delivery system as described herein may be useful fordelivering a bioactive agent to any part on or in a user's body. In someparticular variations, a bioactive agent delivery system as describedherein may be especially useful for delivering a bioactive agenttopically or transdermally to or through a user's skin to a skin layeror bloodstream. Effective topical or transdermally delivery may be aidedby use of a skin delivery membrane such as described herein fortransferring active agent across the skin that is fully or sufficientlywetted to effectively transfer a dose of bioactive agent to a user'sskin. In some variations, a bioactive agent delivery system may beelectronically controlled, programmable, portable, and wearable.

A disposable part may be sufficient or insufficient for an entiretreatment regimen. A disposable part may contain a sufficient amount ofbioactive agent for an entire treatment regimen (e.g., for all requiredtreatments) or may contain only a limited number of doses that providesa partial treatment. Additional amounts of bioactive agent can bedelivered to the user by replacing a spent disposable part in thereusable part with a fresh disposable part.

Having a bioactive agent delivery system with a disposable part mayallow the system to be relatively small or relatively flat and easy towear. For example, a system may be relatively small or flat since adisposable part needs only contain a limited amount of bioactive agentand/or (and as explained in more detail below) a reusable part needsonly be imparted with sufficient force or power for a limited number ofdose deliveries before being recharged. In some examples, a system maybe less than about 20 mm, less than about 16 mm, less than about 15 mm,less than about 14 mm, less than about 13 mm, less than about 12 mm,less than about 11 mm or less than about 10 mm in thickness and may beless than 40 mm, less than 35 mm in length or width, or less than 30 mmin length or width.

In some examples, a system may have less than 1500 mm² or less than 1000mm² top (or bottom) surface area. “Bottom” in this context generallyrefers the part(s) of the system closest to a user. If a system includesa transdermal patch, bottom may refer to the transdermal patch and tothe skin delivery member of a transdermal patch. A surface area of oneside of a skin delivery member may be at least 100 mm², at least 500mm², at least 1500 mm², at least 2000 mm², at least 2500 mm² at least3000 mm² or less than or between any of these numbers (such as at least500 mm² and less than 2000 mm²).

A surface of a bioactive agent delivery device, such as skin deliverymember may have any shape, such as circular, ovoid, rectangular, squareand may be contoured (or able to be contoured) to better fit a user'sskin. Additionally, a disposable part that carries a limited number ofdoses may allow a user to use the doses before oxidation or otherbreakdown processes renders the bioactive agent unsafe or unusable.

As mentioned above, tobacco contains toxic substances that damage aperson's health. Tobacco also contains nicotine and nicotine is highlyaddictive. In some particular examples, a bioactive agent deliverysystem may be useful for delivering a bioactive agent to help a personovercome a nicotine addiction and to stop using tobacco (e.g., to stopsmoking, stop chewing tobacco, etc.). A person who is trying to stopsmoking or stop using another form of nicotine usually experienceshighly unpleasant withdrawal symptoms (e.g., anxiety, cravings,depression, headache, irritability, nausea, etc.). These symptoms can besevere or long lasting. If not addressed, withdrawal symptoms can derailan attempt to quit smoking and a person may continue smoking.

To overcome a nicotine addiction and manage (e.g., minimize oreliminate) withdrawal effects, a user may be gradually weaned fromnicotine by receiving small amounts of therapeutic nicotine (whichamounts may get smaller over time) to reduce symptoms and theneliminating the therapeutic nicotine altogether. Cravings for smoking acigarette (or having another tobacco or other nicotine containingproduct) often come and go over the course of a day and over time (fromday to day, week to week, etc.). Cravings may be especially strong thefirst two-to-three days after giving up smoking.

Some cravings depend on a person's normal daily rhythms and otheractivities in their lives. For example, many people have cravings for acigarette with events that happen daily such as when waking up, aftereating a meal, etc. These cravings may happen at the same or atdifferent times on different days. Many people also have cravings due toother events in their lives such as during a stressful event (e.g.,on-the-job stress, an argument with a person, a traffic accident etc.)that are different from day to day and the timing of these events may behard to predict.

Similarly, pain, whether chronic or acute, often varies during the dayor from day to day. A migraine and other headache may be worse at onetime of the day (such as in the morning) than at another time of day ormay come on unexpectedly. A drug or other bioactive agent may be neededat certain times of day, but may or may not be needed at other times. Asystem as described herein may be configured to provide a bioactiveagent when it is needed by a user. A system may be configured to providea bioactive agent to a user at a pre-programmed time or at an on-demandtime.

To reduce or eliminate withdrawal symptoms (e.g., cravings) and help aperson stop smoking generally requires multiple active agent doses overthe course of a day on multiple days (weeks or months). A bioactiveagent delivery system as described herein may be configured to delivermultiple doses (also referred to as boluses) during the course of a dayand/or for multiple days. A bioactive agent delivery system may beespecially useful to help a user control cravings or other withdrawalsymptoms by delivering a bioactive agent dose (e.g., a dose of nicotine)especially during (or before) a time of day when cravings or withdrawalsymptoms are normally most troublesome (such as delivering a dose duringthe night to prevent cravings upon waking).

In some embodiments of the invention, a reservoir containing thebioactive agent within disposable part is pressurized when, or after,the disposable part connects to the reusable part, and delivery of thebioactive agent is controlled by the reusable part by controlling theoutlet from the reservoir. FIG. 1 shows a block diagram of one suchbioactive agent delivery system for delivering multiple doses of a drugor other bioactive agent to a user in an inexpensive and easy-to-usesystem that reduces risk of accidental bioactive agent delivery oroverdose.

As shown in FIG. 1, a two-part bioactive agent delivery system 2 withreusable part 6 and disposable part 8 work together to deliver aplurality of drug or other bioactive agent doses to user 4. A two-partdelivery system has two parts that can be connected for use together,and then disconnected from each other; the reusable part may thereafterbe used with another disposable part. Such a system may improve safetyor convenience by replacing components that come into contact withbioactive agent, replenishing a bioactive agent supply, supplying a newsupply of absorbent for solvent removal, etc. Such a system may reducecost by reusing some components, such as some of the components that donot come into contact with bioactive agent.

FIG. 1 shows reusable part 6 with housing 10, spring 28, electronicsapparatus 12, and valve driver 13. Housing 10 may wholly but willgenerally at least partially contain, cover, insulate, or protect othercomponents such as electronics apparatus 12, etc., in reusable part 6.It may also wholly or at least partially contain, cover, insulate, orprotect components in disposable part 8 when disposable part 8 isconnected with reusable part 6 for use.

Disposable part 8 generally contains components that come into contactwith bioactive agent, although it may contain additional components aswell. Disposable part 8 and reusable part 6 are configured to connect orotherwise attach to each other in an operative manner. In someembodiments, housing 10 of reusable part 6 and/or housing 36 ofdisposable part 8 may have connectors such as resilient snaps, magnets,detents, etc. to reversibly attach the two housings to each other. Insome embodiments, spring 28 extends from reusable part 6. When reusablepart 6 is connected to disposable part 8, spring 28 engages movablepiston 34 in disposable part 8 (or an intervening element between piston34 and spring 28) to apply a force to movable piston 34, which causespiston 34 to apply pressure to the bioactive agent within reservoir 38.In other embodiments, spring 28 may be located in the disposable part 8and would be compressed and loaded when the reusable part 6 is connectedto disposable part 8.

A reservoir 38 in disposable part 8 contains multiple doses of bioactiveagent for delivery to the user, and reusable part 6 controls dosedelivery from the reservoir to the user 4. In this embodiment, reservoir38 is pressurized when, or after, the disposable part 8 connects to thereusable part. Delivery of the bioactive agent from the pressurizedreservoir 38 is controlled by controlling valve 50 at the outlet fromreservoir 38. Because it does not use a pump, the system of thisembodiment may be more quiet, less expensive, less weight, etc. than asystem with a pump and may be more acceptable to a user.

Spring 28 may include a battery spring or coil spring or another springor component, as long as it can store energy and act to pressurizereservoir 38 in disposable part 8. In other embodiments, spring 28 maybe an air spring, an elastomer, a foam, another fluid spring, a gasspring, another highly compressible material(s), a leaf spring, asponge, or another member that stores energy (e.g., mechanical orpotential energy).

Although referred to as a spring, a function of a spring and its relatedcomponents may be performed by another component such as an inductionsystem, a magnetic system or another system and a bioactive agentdelivery system may or may not have a first (or spring or other spring)as long as it provides or stores potential energy that can be turnedinto kinetic energy. Spring 28 can be any component that can be primed(e.g., compressed against housing 10 via force 30) to store elasticpotential energy.

As indicated above, pressurized bioactive agent can be passivelydelivered to a user from disposable part 8 in a plurality of separatedoses. The first (or second or other) spring may be configured to storesufficient potential energy to deliver a limited number of doses such as1, 2, 3, 4, 5, 6, doses (plus a small amount of reserve energy) and thusmay be relatively small to reduce device size and/or weight. Any springwith a suitable spring constant or maximum spring insertion force thatstores sufficient elastic potential energy to drive appropriate pistonmovement for bioactive agent pressurization (and multiple dose delivery)can be used.

For example, spring 28 may be a spring with a maximum spring insertionforce of less than 30 lbf, less than 20 lbf, less than 15 lbf, less than10 lbf, less than 5 lbf (or in between any of these amounts, such asbetween 10 lbf and 15 lbf, between 9 lbf and 13 lbf, etc.). In someexamples spring 28 is a battery spring or a coil spring with a maximumspring insertion force between 8 lbf and 15 lbf, between 10 lbf and 15lbf, between 11 lbf and 13 lbf, etc.). Spring 28 is generally configuredto provide sufficient force to move the bioactive agent (e.g., themultiple doses of bioactive agent) through the disposable part to anoutlet or user. In some examples, spring 28 may be configured to provideat least 10 N, at least 20 N, at least 30 N, at least 40 N, at least 50N, at least 75 N, at least 100 N, at least 125 N, at least 150 N, atleast 200 N, at least 250 N or less than any of these amounts (e.g.,less than 250 N, less than 200 N, etc.) or anything in between theseamounts. In some examples, spring 28 may provide from 30 N and 50 N,from 50 N to 75 N, from 75 N to 100 N, from 100 to 150 N. For example,spring 28 may be a conical spring providing around 50 N or around 100 N,etc. Spring 28 may be a conical spring or tapered spring such as abattery spring or another spring sufficiently small to fit into thebioactive agent delivery system and provide appropriate force forpressurizing the reservoir or bioactive agent. In some examples, acompressed spring may be shorter than 500 mm, 400 mm, 300 mm, 200 mm,150 mm, 100 mm, 90 mm, 80 mm, 70 mm, 60 mm, 50 mm, 40 mm, 30 mm, or 20mm or least 10 mm, 20 mm, 30 mm, 40 mm, 50 mm, 60 mm, 70 mm, 80 mm, 90mm, 100 mm, 110 mm, 150 mm, 200 mm, 300 mm, or 400 mm or between any ofthese sizes (e.g., longer than 50 mm and shorter than 120 mm). Spring 28may be short enough to fit into a relatively small, wearable bioactiveagent delivery system configured to hold and deliver a limited number ofbioactive agent doses (such as 5 or fewer doses of less than 200 μleach), a spring may be at least 10 mm, at least 20 mm, at least 30 mm,at least 40 mm, at least 50 mm, at least 60 mm, at least 70 mm, at least80 mm, at least 90 mm, at least 100 mm, at least 110 mm, at least 150 mmand/or less than 150 mm (e.g., less than 100 mm, less than 90 mm, lessthan 80 mm, less than 70 mm, less than 60 mm, less than 50 mm, less than40 mm, less than 30 mm, or less than 20 mm) in length. A spring may haveany cross-sectional diameter (e.g., on a first end, on a second end, orbetween the first end and the second end or in the middle of thespring), that provides appropriate force to another component(s) in thebioactive agent delivery system, such as less than 15 mm, less than 10mm, less than 9 mm, less than 8 mm, less than 7 mm, less than 6 mm, lessthan 5 mm, and/or may be larger than any of these amounts (e.g., greaterthan 5 mm, greater than 6 mm, greater than 7 mm, greater than 8 mm,greater than 9 mm, greater than 10 mm, greater than 12 mm, or in betweenany of these sizes (e.g., greater than 7 mm and less than 9 mm indiameter, or greater than 8 mm and less than 11 mm, etc.). For example,a spring for a relatively small, wearable bioactive agent deliverysystem may have a sufficiently small diameter so that the deliverysystem fits comfortably (relatively flatly) against a user's body, butbe long enough to provide sufficient force to deliver a plurality (2, 3,4, 5, 6, or more than 6) doses of bioactive agent through the system. Aspring of a bioactive agent delivery system may be or include a singlespring or may include plurality of springs (e.g., 2, 3, 4, 5, or morethan 5 springs). A system with a plurality of springs may be configuredsuch that an individual spring or two (or more than two springstogether) provide or meet the above indicated parameters. A singlespring may be helpful, for example to minimize device size (length,height or width), such as for acting on a single reservoir or foranother reason. A plurality of springs may be helpful for minimizing thedevice length (e.g., by having more but relatively shorter springsacting on a reservoir) or for acting on a plurality of reservoirs or foranother reason. For example, a bioactive agent delivery device maycontain 1, 2, 3, 4, 5, or more than 5 reservoirs, and each reservoir mayhave an associated spring. As indicated above, a spring may be part ofreusable part. Having a spring in a reusable part may be useful forreducing system cost, since the spring can be reused for easilypressurizing a reservoir(s) in an additional disposable part, etc.Although a spring (or other component) is described herein as being partof a reusable part, it does not need to be part of a reusable part. Insome variations a spring may be part of a disposable part. For example,a spring (e.g., a spring) in a disposable part may allow the bioactiveagent delivery system to be stored pressurized, which may improvebioactive agent shelf life, piston seal shelf life, etc.

Piston 34 may be a disk or other structure that fits (e.g., fits snugly)in reservoir 38 and interacts with spring 28, either directly orindirectly. The spring 28 may act on piston 34 to place a pressure onthe contents of reservoir 38 of at least 1.0 bar, at least 1.5 bar, atleast 2.0 bar, at least 2.5 bar, at least 3.0 bar, at least 3.5. bar, atleast 4.0 bar, at least 4.5 bar, at least, 5.0 bar or less than 12 bar,less than 10.0 bar, less than 8.0 bar, less than 7.0 bar, less than 6.0bar, less than 5.0 bar, less than 4.5 bar, less than 4.0 bar, less than3.5 bar, less than 3.0 bar, less than 2.5 bar, less than 2.0 bar oranything in between these amounts (e.g., between 2.0 bar and 4.5 bar,between 2.3 bar and 4.2 bar, etc.). In some particular examples, adisposable part is configured such that a piston is configured toprovide from 2.3 to 4.6 bar. Pressure from the piston may be greaterthan 1.0×, greater than 1.5×, greater than 2.0×, greater than 2.5×, etc.of atmospheric pressure. Atmospheric pressure is generally around 1.0bar (e.g., 1.067 bar) and pressure within the system is generally higherthan atmospheric pressure in order to allow passive pressure flow fromthe disposable part to the environment. In some variations, a disposabledevice configuration may be chosen to operate at different temperatures,operate upside down (e.g., against the flow of gravity, etc.).

Reservoir 38 is configured to have a variable volume due to movablepiston 34. Initially, the reservoir contains multiple doses of bioactiveagent and the reservoir volume is relatively large. Reservoir 38 maycontain or be configured to contain between 1 μl and 2000 μl ofbioactive agent. Reservoir 38 may contain or be configured to contain atleast 1 μl, at least 10 μl, at least 50 μl, at least 100 μl, at least150 μl, at least 200 μl, at least 300 μl, at least 400 μl, at least 500μl, at least 600 μl, at least 700 μl, at least 800 μl, at least 900 μl,or at least 1000 μl, Reservoir 38 may contain or be configured tocontain a maximum of 2000 μl, 1500 μl, 1000 μl, 900 μl, 800 μl, 700 μl,600 μl, 500 μl, 400 μl, 300 μl, 200 μl, 150 μl, 100 μl, 50 μl or inbetween any of these amounts (e.g., in between 100 μl and 500 μl, inbetween 300 μl and 800 μl, etc.).

Reservoir 38 may contain or be configured to contain a selected numberof doses of defined size, and may include an extra “fill” volume toensure that a sufficient volume is available to deliver all desireddoses (given some normal but minimal/acceptable variability in chambersize, etc. for example based on manufacturing variability). For example,reservoir 38 may contain 3, 4, 5, 6, etc. doses of 100 μl, 125 μl, 150μl, 175 μl, 200 μl plus+/−10% or another pharmaceutically acceptablevariation. Thus in some examples, reservoir 38 contains 5×100 doses (500μl+/−10%), 5×125 doses (625+/−10%), etc. The size of reservoir 38 may bechosen based on the amount of bioactive agent desired, bioactive agentconcentration, bioactive agent solubility, viscosity (e.g., of abioactive agent or a solution containing a bioactive agent), etc.

In this embodiment, valve 50 delivers bioactive agent from reservoir 38into a bolus chamber 46. Bolus chamber 46 has a smaller volume thanreservoir 38 and can therefore be used to control the size of a bolus ordose of the bioactive agent. In this embodiment, bolus chamber 46 has avariable volume due to a piston 51 that moves against the action of aforce provider 53, such as a spring or a hydraulic pressure source. Thevolume of the dose entering bolus chamber 46 from reservoir 38 throughvalve 50 depends on the outlet pressure of reservoir 38, the surfacearea of piston 51, and the force from force provider 53. In someembodiments, these parameters are chosen so that the effective volume ofbolus chamber 46 is constant for every dose received from reservoir 38,such as by moving piston 51 to the limit of its possible travel withevery bolus entering the bolus chamber.

In this embodiment, valve 50 has a second position that communicatesbolus chamber 50 with the system outlet 54 for delivery of the bioactiveagent to the user 4. Thus, valve 50 prevents direct bioactive agent flowfrom the reservoir to the outlet/user, reducing risk of delivering toomuch bioactive agent at any time (e.g., reducing risk of an overdose).

Electronics apparatus 12 is configured to control timing of delivery ofbioactive agent doses to user 4 by disposable part 8. Electronicsapparatus 12 includes a controller such as a computer, microprocessor,printed circuit board (PCB), processor, or another electronic deviceconfigured to control bioactive agent delivery. Delivery time of abioactive agent dose controlled by electronics apparatus 12 maypre-programmed (e.g., programmed ahead of time) or may be controlled atthe time of delivery (e.g., may be delivered on-demand). Electronicsapparatus 12 is also configured to receive user input 24 such as from afinger, hand, a mobile device (e.g., Bluetooth, smartphone, Zigbee,etc.) voice command or from another input; input may be set-up ahead oftime or may be an “on-demand” input. Electronics apparatus 12 controlstiming of bioactive agent delivery by controlling valve driver 13 (andtherefore valve 50) and allowing or preventing bioactive agent deliveryto a user by controlling the timing bioactive agent flow from reservoir38 to bolus chamber 46 and from bolus chamber to outlet 54. As shown inFIG. 1, electronics apparatus 12 is in reusable part 6, but in otherembodiments in may be in the disposable part.

A bioactive agent delivery system as described herein may be configured(e.g., via electronics apparatus 12) to deliver a bioactive agent atregular times and/or at irregular times, and during one or more than onedays. A regular time may be a regular time during a day (e.g., every 2hours, every 4 hours, etc.) or a regular time on different days (e.g.,just before waking up, at meal time, etc.). A bioactive agent deliverysystem may be configured (e.g., via electronics apparatus 12) to delivera bioactive agent to a user at one or more predetermined times (e.g., itmay be pre-programmed). A bioactive agent delivery system may allow auser to request delivery of a bioactive agent, and bioactive agent mayalso or instead be delivered “as-needed” during a day(s), such as basedon a user request (e.g., from user input 24). For example, a personusing a bioactive agent delivery system for smoking cessation mayrecognize they are experiencing a craving for a cigarette and mayrequest delivery of a dose of a smoking cessation agent to help controlthe craving and prevent them from smoking a cigarette. For example, apatient may request a dose of bioactive agent such as codeine, fentanyl,ibuprofen, methadone, or another agent for pain management or othertherapeutic or prophylactic use as needed. In some examples, a systemmay count or otherwise determine how much bioactive agent a user hasreceived in a given time period. Based on determination such as this, asystem may determine that a user is eligible to receive a dose ofbioactive agent and may deliver a bioactive agent dose to the user inresponse to the request (e.g., by signaling valve driver 13 to move anddeliver a dose to user 4). In some examples, a system may determine thata user is not eligible to receive a dose and may not deliver a dose inresponse to a user's request (e.g., may not signal valve driver 13 tomove). For example, a system may count or otherwise determine that auser has received as much bioactive agent as allowed in a given timeperiod; an additional dose may be an overdose or otherwise dangerous. Abioactive agent delivery system may be pre-programmed with bioactiveagent delivery times, such as with pre-set times (e.g., by or asdetermined by a manufacturer, pharmacist, medical professional, etc.) oras customized by the user. For example, a system may be programmed toprovide a smoking cessation agent before a person's craving is likely tostart or become strong. Thus a system may be programmed to deliver adose based on an expectation that it may be needed (before or withoutsuch a need actually appearing). Such programming may be based on theuser's history or habits, data or statistical analysis of other users,etc. For example, a user may previously have experienced cravings tosmoke upon waking up from sleep and a system may be programmed toprovide a dose of nicotine or other smoking cessation agent before oraround the time the user expects to awaken.

Electronics apparatus 12 generally includes a power source (battery) forproviding power to the printed circuit board, computer or otherelectronic component in electronic apparatus 12. A power source may alsoprovide power to valve driver 13 to change the configuration of valve 50and move bioactive agent through disposable part 8 or to user 4.

Reusable part 6 includes a valve driver 13 for controlling bioactiveagent flow in the disposable part when the reusable part 6 is connectedto the disposable part 8 by controlling operation of valve 50 indisposable part 8. Valve driver 13 may be an electromechanical actuatorcontrolled by (and receiving power from) electronics apparatus 12. Avalve driver may be any type of valve driver that can move the valve ormove part of the valve (e.g., the valve core) at least from a firstposition to a second position to control bioactive agent flow throughdisposable part 8. A valve driver may be or may include a geared DCmotor such as DC motor with a 4-stage planetary gearbox or another valvedriver that is efficient at getting mechanical work from electricalenergy at the scale of the bioactive agent delivery system. A small orlightweight valve driver that consumes minimal energy may be especiallyuseful to minimize the size or weight of the valve driver and/or thepower source such as a battery in a wearable system. An efficient valvedriver may minimize the frequency with which a power source is rechargedor replaced. A valve driver may include a pair of shape-memory alloywires acting against a return spring or another driver generally with alow energy requirement that can control valve 50 to control bioactiveagent flow in disposable part 8. A valve driver may include a voice coilor another driver that is lightweight or takes up relatively minimalspace. A valve driver may include a shape-memory alloy driver or anotherdriver that is quiet (or silent) or creates minimal (or undetectable)vibration or other disturbance to a user. A valve driver may include astepper motor or another driver that limits valve (or part of a valve)movement, such as in a limited range or motion, a limited number ofpositions, or in only specific positions such as including and inbetween a first position and a second position. Any of the abovementioned valve drivers may be used in any bioactive agent deliverysystem but may be especially useful in a portable or wearable bioactiveagent delivery system.

Bioactive agent delivery to a user using the bioactive agent deliverysystem shown in FIG. 1 generally takes place in four steps. First,bioactive agent in reservoir 38 is pressurized (e.g., above atmosphericpressure) due to the action of spring 28 on piston 34 (directly orindirectly). Second, movement of valve 50 to a first position permits asingle dose of bioactive agent to fill bolus chamber 46 by moving piston51 against the action of force provider 53. The surface area of pistonfacing the bolus chamber and the spring force of force provider 53 arechosen so that the pressure of the bioactive agent flowing out ofreservoir 38 is high enough to move piston 51 against the action offorce provider 53 to permit the bioactive agent to enter the boluschamber. Third, valve 50 moves to a second position to permit the singledose of bioactive agent in bolus chamber 46 to flow to outlet 54.Pressure provided by the action of force provider 53 against piston 51causes the bioactive agent to flow from the bolus chamber 46 throughvalve 50 to the outlet 54. Fourth, the dose of bioactive agent flowsfrom outlet 54 through a delivery path 57 to user 4 where the bioactiveagent can have a bioactive (e.g., prophylactic or therapeutic) effect.Delivery path 57 may include, e.g., a transdermal patch or membrane, acannula, or other patient interface.

In some variations, one or more wall(s) of the reservoir 38 in thedisposable part may be a flexible or compressible (e.g., resilientlyflexible and capable of returning to an original size after beingcompressed or collapsible and unable to return to an original size) andthe walls may be compressed in response to force from spring 28.

In some variations, a flexible reservoir in the disposable part may berelatively flexible over substantially its entire body and the entirebody may be compressed in response to an applied force. In somevariations, a flexible reservoir may include a first region that isinflexible and a second region that is relatively flexible such that apiston or other compressive structure may act on the flexible reservoirand collapse or compress a portion the flexible reservoir (e.g., aflexible portion) to pressurize bioactive agent. For example, a flexiblereservoir may be a bag or bladder, or another compressible structureable to contain bioactive agent, and a piston or other force (e.g., onthe outside of the bag or bladder) may act to compress the bag orbladder to pressurize bioactive agent. During reservoir and bioactiveagent compression by piston 34, the bioactive agent flow pathway betweenthe reservoir and the bolus chamber may be open or closed.

Although a disposable part is referred to above as having a reservoir, adisposable part may have one reservoir, or may have a plurality ofreservoirs (e.g., 2, 3, 4, or more than 4 reservoirs). A plurality ofreservoirs in a disposable part may be joined together or may bestandalone components. Each reservoir may contain 1, 2, 3, 4, 5 or morethan 5 doses of bioactive agent. As indicated elsewhere, a bioactiveagent delivery system may contain 1 or more than one spring that can acton a reservoir, and one spring may act on one reservoir to pressurizebioactive agent and each reservoir may have a single spring pressurizingit or a single spring may act on a plurality of reservoirs. Active agentin a disposable part (e.g., in a reservoir) may be pre-loaded with abioactive agent or may not be pre-loaded. A reservoir may be loaded by anurse, pharmacist, user, etc.). A disposable part that is not pre-loadedmay for example be easier to manufacture or to store. For example,different components of a disposable part (including bioactive agent)could be manufactured at different times or as needed; a single type ofdisposable part may be usable with different bioactive agents and aparticular bioactive agent can be loaded into the disposable part onlyas needed, etc.).

In some variations, a disposable part may be configured to minimizetampering. A disposable part may be configured to substantially preventa user from placing a bioactive agent (e.g., an illegal drug or otheragent) into a disposable part. For example, a reservoir may not have abioactive agent loading port readily available for a user to use to loadbioactive agent. For example, a reservoir may be made from or covered bya hard material (such as a plastic or stainless steel) that is difficultto penetrate with a syringe or other bioactive agent loading device.These or other disposable part configurations may be relativelytamper-proof. They may prevent a user from using a disposable part for adifferent purpose (e.g., illegal drug use, overdose, etc.) than itsintended (therapeutic or prophylactic) purpose.

A valve for use in a disposable part may be a plug valve or gate valveor another valve that can control (e.g., at different times allow orprevent) fluid flow between reservoir 38 and bolus chamber 46 or betweenbolus chamber 46 and outlet 54. A valve is generally configured so thatbolus chamber 46 is only connected (e.g., a flow path is open) toreservoir 38 or to outlet 54 but not both simultaneously. A valve may bea 3-way valve such as a gate valve or a plug valve or another valve thatminimizes risk of overdose or unintended medication delivery to thepatient for example by preventing a direct flow path from reservoir 38to outlet 54 (user). A valve may be configured such that there is nodirect flow path between a bioactive agent reservoir and an outlet to auser and bioactive agent cannot flow directly from the reservoir to anoutlet (e.g., regardless of what configuration a valve is in).

The valve 50 may have a valve body and a valve core that moves relativeto the valve body and controls the flow of bioactive agent through thevalve. A valve body may be configured to stay in a position(s) relativeto the valve core and relative to other components in the disposablepart and/or reusable part without requiring a force to hold it in theposition(s). In some variations, a valve may have a rotatable coreinside a valve body and one, two (or more) hollow passageways throughthe valve core configured for bioactive agent to flow through. In somevariations, a valve (and/or valve driver) may be configured so that thevalve (e.g., valve core) has limited movement. Such a configuration maybe useful to minimize the amount of energy required to operate thevalve, improve valve accuracy (by positioning the valve only in alimited number of desired locations), etc. This may be useful to reducesystem complexity, system size (e.g., power source size), system weight(e.g., power source weight), eliminate or reduce energy recharging, etc.This may be especially useful in a wearable bioactive agent deliverysystem to minimize size and improve user acceptance.

In some examples, a rotatable valve (or rotatable valve core) may rotate180° or fewer degrees, 135° or fewer degrees, 90° or fewer degrees, 80°or fewer degrees, 70° or fewer degrees, 60° or fewer degrees, 50° orfewer degrees, or 40° or fewer degrees. In some particular examples, avalve core may be configured to rotate between two different positions,such as rotating from about 60° to about 90° to move the valve between afirst configuration and a second configuration. Thus a valve may moveclockwise and counterclockwise.

For example, a 3-way valve (e.g., an “L” shaped 3-way valve) may have avalve body with three connections to the disposable part (e.g., oneleading to the reservoir, one leading to the bolus chamber, and oneleading to the outlet) and a valve core with two ports connected by apassageway through a hollow member (e.g., passageway may be “L” shaped)in the valve. A 3-way valve has two flow patterns: a first flow patternallowing bioactive agent flow from the reservoir to the bolus chamber inwhich a first port is open to the reservoir and a second port is open tothe bolus chamber (with no bioactive agent flow to the outlet/user) andbioactive agent flows through the channel from the reservoir to thebolus chamber through a first flow path, and a second flow pattern fromthe bolus chamber to the outlet in which the first port is open to theoutlet and the second port is open to the bolus chamber (with nobioactive agent flow to the reservoir) and bioactive agent flows throughfrom the bolus chamber to the outlet through the channel.

A disposable part may include a single 2-position, 3 port plug valve. Inan L-shaped 3-way valve, there is no direct bioactive agent fluid flowpathway from the reservoir to the outlet, and risk of overdose orunintended bioactive agent delivery to the user is greatly reduced. Insome variations a 3-way or other valve may also be in third positionrelative to the rest of the disposable chamber and prevent bioactiveagent flow (e.g., prevent any flow) between the reservoir, boluschamber, and outlet; the valve may be completely closed to bioactiveagent flow. In some other examples, a valve may be a “T” shaped 3-wayvalve, with three connections to a disposable part in a valve body andthree ports connected by a passageway through a hollow member in thevalve core. A “T” shaped valve may be configured and placed in abioactive agent delivery system such that there is no direct flowpathway between the reservoir and outlet in any position that the valve(e.g., the valve core) can take.

In some examples, a disposable part may be configured so that bioactiveagent could flow in either direction between the reservoir/bolus chamberor bolus chamber/outlet (e.g., it may lack a non-return valve or otherstructure to prevent bioactive agent flow from the bolus chamber back tothe reservoir), but is prevented from flowing from the bolus chamberback to the reservoir due to the higher reservoir pressure (or in thesecond example, higher bolus chamber pressure) compared with the boluschamber pressure (or in the second example, outlet pressure).

A valve may be configured to minimize friction between the valve and thefluid (bioactive agent) flowing through it. In some examples an internaldiameter of a hollow of a valve may be the same or close to the same asan internal diameter of a first flow passageway (e.g., between areservoir and a bolus chamber) or a second flow passageway (between abolus chamber and an outlet).

In some examples, a valve (e.g., a valve core) may be bi-stable and maybe stable (resting) in either of two positions. A 3-way valve may bebi-stable, for example, in either of two configurations: in a firstconfiguration with the valve core in a first position so that apassageway is open in the valve between the reservoir and the boluschamber (and closed to the outlet), or in a second configuration withthe valve core in a second position so that a flow path open between thebolus chamber and the outlet (and closed to the reservoir). A bi-stablevalve stays in one of its configurations until it is acted on by a forceto change its configuration (e.g., in the example of a 3-way valve tomove the valve core from a first position to a second position). Poweris not required to maintain a bi-stable valve in a particularconfiguration. Power is applied to move a valve between differentconfigurations (e.g., from a first position to a second position or asecond position to a first position, such as described above). A valvemay remain in a position until it is acted on, such as acted on by valvedriver 13. A valve may be between 5 mm and 20 mm in length or any lengththat is able to control bioactive agent fluid flow and fit into thedisposable part. In some examples a valve is between 8 mm and 15 mm, 10mm and 12 mm, etc. A valve cross-section (e.g., a diameter if a valvehas a substantially circular cross-section) may be between 0.5 mm and 5mm, such as between 0.7 mm and 2.0 mm, between 0.8 mm and 1.5 mm, etc.).

In general, the dosing volume (e.g., effective volume of the boluschamber when it is filled with bioactive agent) is highly repeatableand/or reproducible such that each dose is within a pharmaceuticallyacceptable range. Due to small manufacturing differences or otheracceptable variances, doses may vary in volume or activity by apharmaceutically acceptable amount (such as by +/−5%, +/−10%, +/−15%,etc.). A bolus chamber may, for example, be configured to receive (e.g.,a swept volume of a bolus chamber may be) between 1 μl and 1000 μl ofbioactive agent for each dose. A bolus chamber may receive at least 1μl, at least 10 μl, at least 50 μl, at least 100 μl, at least 150 μl, atleast 200 μl, at least 300 μl, at least 400 μl, at least 500 μl, atleast 600 μl, at least 700 μl, at least 800 μl, at least 900 μl, or atleast 1000 μl. A bolus chamber may be configured to receive a maximum of1000 μl, 900 μl, 800 μl, 700 μl, 600 μl, 500 μl, 400 μl, 300 μl, 200 μl,150 μl, 100 μl, 50 μl or in between any of these amounts (e.g., inbetween 50 μl and 200 μl, in between 100 μl and 300 μl, etc.). In someexamples, a bolus chamber is configured to hold between 100 μl and 300μl and contains nicotine. A dose of nicotine may be, for example 100 μl,125 μl, 150 μl, 175 μl, 200 μl etc. or in between any of these amounts.A bolus chamber size may be chosen based on the amount of bioactiveagent desired, bioactive agent concentration, bioactive agentsolubility, viscosity (e.g., of a bioactive agent or a solutioncontaining a bioactive agent), etc. Although for simplicity the boluschamber is referred to herein as receiving and delivering a dose ofbioactive agent, the bolus chamber could instead receive a partial dose(e.g., 1/Nth of a dose), and deliver multiple cycles of partial doses(e.g., N cycles having 1/Nth of a dose). Thus a dose could be deliveredin 1, 2, 3, 4, 5, or more than 5 cycles.

Outlet 54 is an opening fluidly connected with bolus chamber 46 viavalve 50. Outlet 54 generally delivers bioactive agent to a deliverycomponent (such as a transdermal patch, microneedle, etc.) for bioactiveagent delivery to user 4. A delivery component may be integral with orseparated from a disposable part. As indicated above, bioactive agentpressure in bolus chamber 46 is greater than the pressure at outlet 54and/or a delivery component or user, which is generally at or aroundatmospheric pressure.

When a flow path is opened between bolus chamber 46 and outlet 54 byvalve 50, a dose of bioactive agent flows from the area of higherpressure in the bolus chamber) to the area of lower pressure (outside ofthe outlet). After flowing through outlet 54, a bioactive agent may bedelivered to a user by any appropriate delivery method. For example,bioactive agent may be delivered using iontophoresis (e.g., with aniontophoretic patch), microneedles, a needle, a topical patch (e.g.,configured for delivery of a bioactive agent local at the site ofapplication (skin) without resulting in a significant bioactiveconcentration in the blood), a transdermal patch, etc.

Bioactive agent flow from bolus chamber 46 through outlet 54 to adelivery component may take place very quickly. Bioactive agent flowthrough outlet 54 may be faster than is flow generated by a pump (e.g.,a mechanical device for moving bioactive agent). Rapid delivery to adelivery component may be especially useful for wetting a membrane fortransdermal or topical bioactive agent delivery. Rapid flow may causeeffective wetting of a topical or transdermal membrane (e.g.,essentially the entire membrane) without significantly forcing bioactiveagent through the membrane (during the wetting process). Rapid wettingand absorption of a bioactive agent through a user's skin may minimizeevaporative (solvent) loss and provide for better or more consistentbioactive agent delivery to a user.

In some variations, and as described in more detail below, a dose ofbioactive agent may be delivered through an outlet (to a deliverycomponent such as to a skin delivery member of a transdermal patch asdescribed below) in less than 5 seconds, less than 4 seconds, less than3 seconds, less than 2 seconds, less than 1 second, less than 0.5seconds, less than 0.1 seconds, etc. Thus a bioactive agent deliverysystem may be configured to provide 1 or a plurality of doses (e.g., 2,3, 4, 5, 6 or more doses) to an outlet or user within such time frames.For example, a dose of nicotine may be delivered in less than 2 seconds,1 second, or 0.5 seconds and may rapidly wet a skin delivery member toprovide rapid bioactive agent transfer to a user. Such transfer may beuseful to quickly provide a nicotine dose to control a craving for acigarette. In some variations, a dose of bioactive agent may bedelivered through an outlet (to a delivery component such as to a skindelivery member of a transdermal patch as described below) over a longertime period such as at least 1 minute, 5 minutes, an hour, two hours,etc. Thus a system may behave as timed release or extended release.

In some particular examples, a fluid space connects outlet 54 and amembrane of a transdermal patch configured to contact a user's skin, andbioactive agent flows from outlet 54 to the membrane and the membrane(essentially the entire membrane) is wetted in less than 5 seconds, lessthan 1 second, less than 0.5 seconds, less than 0.1 seconds, etc. Anyparameter of the system may be chosen to control the amount of time forbioactive agent delivery from the bolus chamber (or outlet) to a skindelivery membrane or another user delivery member. Skin deliverymembrane features (e.g., membrane material, membrane hydrophilicity,membrane size, channels, pore size, etc.), other fluid distributionfeatures (such as the presence of channels or another fluid distributionfeature on another membrane configured to move bioactive agent betweenthe bolus chamber and the skin delivery membrane, diameter or size ofany channels or other fluid distribution features), bioactive agentpressure, spring parameters (size, strength, etc.) or another systemfeature may be chosen to control wetting efficiency, such as wettingtime, wetting speed, depth of wetting or another parameter.

A reusable part may be used with a single disposable part, but ingeneral will be used with a plurality of disposable parts. In somevariations, a disposable part can be refilled or recharged and reused.Bioactive agent, a power source (if present), etc. may be replaced useddisposable part as appropriate.

In some embodiments, a disposable part (e.g., bioactive agent and areservoir) may be pressurized by the action (of a user) of loading adisposable part into or onto a reusable part, e.g., loading a disposablepart into a reusable part provides a pressurization force. As describedabove, compressing the spring provides a force on the piston for thepiston to pressurize the reservoir and bioactive agent in the disposablepart. Taking advantage of providing a force upon loading the disposablepart may minimize the size or weight of a bioactive agent deliverysystem and make the system more comfortable or easier to use. Forexample, by using the action of the user loading the disposable part toprovide a force, a large or heavy pump and associated components such aspower for the pump, etc. is not required for pressurizing bioactiveagent.

A bioactive agent delivery system as described herein is generallyconfigured without a direct pathway between the reservoir and outlet tominimize a risk of bioactive agent overdose: the large amount ofbioactive agent in the reservoir cannot be directly delivered to a user.In some variations, a disposable part may be configured so that a valve(e.g., a valve core) in the system can be in any (e.g., two or more) ofits possible configurations when a disposable part is loaded into areusable part. Such a system may be more convenient or easier for a userto use. For example, a user may be able to replace a disposable part atwhatever time it is convenient for them to do so without being concernedwith checking or changing a valve position before doing so. Such asystem may minimize device size or weight which may be an advantage suchas for a wearable system. For example, a system may readily use abi-stable or other valve that requires minimal power to operate (sincethe valve can stay in whatever position it is in and the disposable partcan be replaced regardless of the valve configuration. Power consumption(and power source size or weight, overall system size or weigh, etc.)may be minimized.

FIGS. 2 and 3 show a two-part bioactive agent delivery system 2 withreusable part 6 and disposable part 8 that work together to deliver drugor another bioactive agent to user 4. Reusable part 6 includes housing10, electronics apparatus 12, valve driver 13, and spring 28 such asdescribed above. Disposable part 6 includes piston 34, valve 50,reservoir 138, bolus chamber 146, piston 142, and outlet 54. Some ofthese are described above with reference to FIG. 1 and others aredescribed below.

To drive fluid flow through the system, piston 142 is fluidly connectedto reservoir 138 by hydraulic flow path 140 to provide a pressurizingforce for bolus chamber 146. Bolus chamber 146 is fluidly connected viavalve 50 either with reservoir 138 by reservoir flow path 48 or withoutlet 54 by outlet flow path 52. In both cases, bioactive agent flowsfrom bolus chamber 146 to valve 50 by bolus chamber flow path 44.

As shown in FIG. 3, piston 142 is actually a pair of pistons connectedby a shaft. Smaller piston 116 has a face in fluid communication withreservoir 138, and larger piston 112 has a face in fluid communicationwith accumulator or bolus chamber 146. Seals 253 and 255 surroundpistons 112 and 116, respectively. Because the surface area of piston116 is smaller than the surface area of piston 112, the dual pistonswill move to the position shown in FIG. 3 when valve 50 connectsreservoir 138 with accumulator or bolus chamber 146. When valve 50 isturned (e.g., under action of the valve drive 13 shown in FIG. 2) toconnect bolus chamber accumulator 146 with outlet 54, the lower pressureat the outlet will permit dual piston 142 to move under the influence ofthe force exerted on piston 116 by reservoir 138 to dispense thecontents of accumulator 146 to outlet 54.

As in the earlier embodiments, accumulator or bolus chamber 146 is sizedto contain a single dose of the bioactive agent, and reservoir 138 issized to contain multiple doses. Seals 253 and 255 provide frictionalstability to the system in addition to preventing leaking of bioactiveagent around pistons 116 and 112. The surface area of piston 112 facingaccumulator or bolus chamber 146 may be 1.1×, 1.5×, 2.0×, etc. largerthan the surface area of piston 116 facing reservoir 138. A patientinterface may be provided at outlet 54, as discussed above with respectto FIG. 1. In addition, user input may be provided to reusable part 6 asdiscussed above with respect to FIG. 1.

FIG. 2 also shows electronics apparatus 12 and valve driver 13 inreusable part 6. Electronics apparatus 12 is configured to control valvedriver 13 which in turn controls the configuration of valve 50. Valve50, as described above, controls the flow of bioactive agent throughdisposable part 8. Valve driver 13 includes wire 62, lever 60, andreturn spring 70. Wire 62 is a shape-memory alloy wire configured toshape-change from a first shape to a second shape (such as first andsecond lengths) in response to current 66 from electronics apparatus 12.When wire 62 moves from its first shape to its second shape, it movesvalve 50 from a first position to a second position. As described above,the position of valve 50 controls how bioactive agent fluid flowsthrough the system.

FIG. 4A shows a block diagram of a two-part bioactive agent deliverysystem for delivering multiple doses of a drug or other bioactive agentto a user with an inexpensive and easy-to-use system that reduces riskof accidental bioactive agent delivery or overdose, and FIG. 5 showsaspects of the disposable part of that embodiment. FIG. 4A shows in thereusable part 6 another embodiment of a valve driver for controlling avalve in a bioactive agent delivery system. FIG. 4A shows valve driver13 with motor 94, gearbox 90, and clutch 58. FIG. 4A shows motor 94(such as a DC or other motor) driving 4-stage planetary gearbox 90 torotate valve core 406 in valve body 74. Such a driver may generaterelatively more torque and a higher turn angle, while having arelatively low current draw and low total energy usage.

In particular, FIGS. 4A and 5 show an embodiment of the disposable partwith a two spring system. As described above for FIG. 1, the systemgenerally operates based on passive pressurization that drives bioactiveagent flow through the system. In this embodiment, a spring 382 acts ona movable piston 386 to apply pressure to the contents of bolus chamber346. A valve driver 13 in reusable part 6 moves valve 50 from a positionin which the outlet of pressurized reservoir 38 communicates with boluschamber 346 to a position in which bolus chamber 346 communicates withoutlet 54. When bolus chamber 346 is in communication with reservoir 38,piston 386 moves against the action of spring 382 to allow bolus chamber346 to fill. When bolus chamber 346 is in communication with outlet 54,spring 382 moves piston 386 to dispense the contents of bolus chamber346 to the outlet. A seal 153 surrounds the edge of piston 386. Otherelements of this embodiment are the same as in the embodiment of FIG. 1.

In some variations, and in comparison with the hydraulic embodimentdescribed above, this two-spring embodiment has lower friction due tohaving one fewer sliding seals (e.g., a first seal but not a secondseal) on piston 386, and the system can function at a lower (initial)pressure. Such a variation may allow use of a relatively weaker mainreservoir spring. This may be useful, for example, for reducingstructural load on the reusable part (e.g., reducing spring force on thehousing). Such a variation may also make it easier (e.g., for the user)to insert the disposable part into the reusable part.

FIG. 4B shows a system similar to that of FIG. 4A but adding transdermaldelivery and solvent recovery features that can be used for transdermaldelivery of bioactive agent to the user 4. A transdermal delivery systemmay be as described in U.S. Pat. No. 8,440,221 to Zumbrunn et al., U.S.2014/0207047 to DiPierro et al. or as known in the art. A bioactiveagent for transdermal delivery may be any those described elsewhereherein or as known in the art.

FIG. 4B shows bolus chamber 346 configured to deliver bioactive agent tooutlet 54 and to transdermal delivery membrane 204. A bioactive agentmay be dissolved in a solvent for delivery to a user, and the rate oftransdermal delivery of the bioactive agent may be controlled by movingsolvent to control the concentration of the bioactive agent solution.This embodiment therefore includes a solvent removal feature including,e.g., an absorbent or a desiccant for removing solvent from the solutionin or above the transdermal membrane 204. A gas permeable membrane 210permits gaseous solvent to pass through to the desiccant 222 but doesnot allow the liquid bioactive agent solution to pass. Skin deliverymembrane 204 is generally a porous membrane such as a polypropylene orother substrate such as described herein or as known in the art thattransfers bioactive agent to the skin, generally contacting the skin ofuser 4 to facilitate transfer. In some examples, removing solvent maydry skin delivery member 204, preventing (further) bioactive agenttransfer to user 4 and thus removing solvent may be a mechanism to stopbioactive agent delivery to user 4. In some examples, bioactive agentfrom a first dose may move across skin of user 4 and leave solventbehind. Thus, when bioactive agent from a second dose is delivered tothe transdermal delivery membrane, the concentration of bioactive agentin the second dose may be diluted by solvent remaining in and around thetransdermal delivery membrane from the first dose.

An absorbent for use with a transdermal patch as described herein may bean absorbent gel, blotting paper, paper, other polymer, silica gel orother material that readily soaks up or holds a fluid media such as asolvent liquid or vapor. An absorbent generally behaves as a physicalsponge. An absorbent may be any structure or shape such as a singlepiece or a plurality of pieces. An absorbent may be an amorphousmaterial or a formed material, and may be a block, a layer, a sheet, aplurality of sheets, a plurality of particles and so on. A desiccant maybe used instead or in addition to the absorbent.

A solvent for a bioactive agent may include a single component ormultiple components such as alcohol, water, or another solvent thatreadily vaporizes. One or more than one component may vaporize and beabsorbed by absorbent. A vapor/gas permeable membrane may containdiscrete pores that extend from one side of the membrane to the otherside and allow gas to flow through. The size of these pores generallyvaries within a given membrane. In some examples, average or effectivepore size in gas permeable membrane 210 may be at least 1 μm, at least 2μm, at least 3 μm, at least 4 μm, at least 5 μm, at least 6 μm, at least7 μm, at least 8 μm, at least 9 μm, at least 10 μm, at least 15 μm, atleast 20 μm, or at least 30 μm. In some examples, maximum or averagepore size in membrane 205 may be less than 30 μm, less than 20 μm, lessthan 16 μm, less than 15 μm, less than 10 μm, less than 9 μm, less than8 μm, less than 7 μm, less than 6 μm, less than 5 μm, less than 4 μm,less than 3 μm or less than 2 μm or in between any of these amounts(such as at least 1 μm but less than 16 μm, at least 2 μm and less than15 μm, etc.).

As mentioned above, it is generally desirable to prevent or minimizeliquid flow through gas permeable membrane 210 (e.g., from thetransdermal delivery membrane to the absorbent and/or desiccant).Pressure (such as pressure from bioactive agent delivery from outlet 54)may be sufficient to force liquid through a gas permeable membrane.Thus, a bioactive agent delivery system pressure and a membrane with anappropriate pore size may be chosen to allow vapor to flow through themembrane but effectively prevent liquid (e.g., a solvent) from flowingthrough. For example, bubble point test that tests the integrity of amembrane can be used to determine maximum pore size in a membrane. Abubble point test generally determines the minimum pressure, for a givenwetted membrane, at which bubbles of air flow through the wettedmembrane. A bubble point test may be performed using, for example,American Society for Testing and Materials Standard (ASTM) MethodF316-03(2011) or another test. In some examples, the pressure ofbioactive agent released by the bioactive agent delivery system is belowthe bubble point of gas permeable membrane 210.

FIG. 6 shows an embodiment of a shape-memory valve driver for use in thereusable part, and a valve plug for use in the disposable part, of atwo-part bioactive agent delivery system according to this invention.Valve plug 416 corresponds to valve 50 in the disposable part describedin the embodiments above. Extending from valve plug 416 are first pin408 and second pin 410 that are adapted to extend from the disposablepart into the reusable part of the two-part delivery system when the twoparts are connected.

FIG. 6 also shows valve driver 400 (corresponding to valve driver 13described in earlier embodiments) with first wire 402 made of a shapememory allow, a second wire 412 also made of a shape memory alloy, leafspring 404, and leaf spring 414, all of which are disposed in thereusable part of the two-part delivery system. First wire 402 isconfigured to act on spring 404 and second wire 412 is configured to acton spring 414. In response to a signal from the system's electronicsapparatus to fill a bolus chamber with a dose of bioactive agent,electrical current from the electronics apparatus passes through firstwire 402 which heats and shortens first wire 402, which in turn bendsspring 404 to move and rotate first pin 408 on valve plug 416 into afirst position (e.g., opening a flow path through the valve between apressurized reservoir and the bolus chamber). When the electricalcurrent ceases, first wire 402 cools and lengthens, and spring 404returns to its first position. Due to internal friction, however, valveplug 416 remains in the position it is in until second wire 412 isheated. When a dose of bioactive agent should be sent to user,electrical current is sent to second wire 412, which heats second wire412, pulling second pin 410 of valve plug 466 into a second position andopening a flow path between the bolus chamber and the delivery systemoutlet, simultaneously closing the flow path between the bolus chamberand the reservoir. Spring 404 and spring 414 may be leaf springs, aresilient polymer or another material as long as it is movable by thewires and can rotate the valve plug. First wire 402 and second wire 412can be made from a shape-memory material or another material as long asthey can respond to a current and move (respectively) spring and spring.

FIG. 7 shows another embodiment of a shape-memory valve driver 430 foruse in a two-part bioactive agent delivery system. As in the embodimentof FIG. 6, extending from a valve body 416 in a disposable part are pins408 and 410. Pins 408 and 410 may be inserted into the reusable part ofthe two-part system to engage a rotor 420 configured to rotate about ashaft 422 mounted within the housing of the reusable part of the system.Shape memory alloy wires 402 and 412 may be selectively energized toshorten wire 402 or wire 412 to move the valve plug 416 from oneposition to another, as described above.

FIG. 8 shows another embodiment of a valve driver for a two-partbioactive agent delivery system. A motor 94 within the reusable part ofthe two-part system may be activated to turn a drive shaft 96 extendingfrom the reusable part into a corresponding fitting 98 in the valve body416 in the disposable part. As shown, the fit between shaft 96 andfitting 98 is tapered. A motor and corresponding valve may be configuredto have rotational alignment or to not have rotational alignment. Insome examples, rotational alignment is not required and the motor andvalve core can be fitted together in any orientation relative to oneanother. In some examples, a valve driver may have a feature (such as aspline) to aid in rotational alignment between the valve driver andvalve. A valve may also or instead have a feature (such as a groove) toaid in rotational alignment with the valve driver. A conical fit may bemore tamper-resistant. A valve driver with a motor may be especiallyuseful in a wearable or portable bioactive agent delivery system.

FIGS. 9A-9E show one embodiment of a bioactive agent delivery systemwith reusable part 6 and a disposable part 8 such as described in FIG. 1above. The reusable part 6 includes a housing 10 containing valve driver13, spring 28, spring 53 and the control electronics. Disposable part 8has the dosing or bolus chamber 46, the piston 51 for the bolus chamber,reservoir 38, reservoir piston 34 and valve 50. In this example, theparts of the two-part delivery system that come into contact withbioactive agent are in disposable part 8.

FIG. 10 shows another embodiment of a two-part bioactive agent deliverysystem such as described in FIG. 1 with reusable part 6 and disposablepart 8 that mate and work together. In general the reusable part 6 anddisposable part 8 are configured to be readily separable from each otherso that a first disposable part can be removed from the reusable part,and the reusable part can be used with a second disposable part.

FIGS. 11A-C show yet another embodiment of a two-art bioactive agentdelivery system. FIG. 11A shows a perspective view of the assembleddelivery system showing disposable part 8 inserted beneath a shroud orhousing 10 of reusable part 6. FIG. 11B shows a partially cut awayperspective view of the reusable part 6 in this embodiment with areservoir spring 28, a reservoir plunger 34 a (for interacting with thepiston in the reservoir in the disposable part), a bolus chamber spring53, a bolus chamber plunger 51 a (for interacting with the piston of thebolus chamber in the disposable part) valve motor 94 for turning a valvein the disposable part to control bioactive agent delivery between thereservoir and bolus chamber, and between the bolus chamber and thesystem outlet. FIG. 11C shows a side longitudinal view of the bioactiveagent delivery system showing many of the same elements of the reusablepart 6 along with some of the system electronics, such as battery 14,PCB 18, and user interface 22.

FIG. 12 shows another embodiment of a two-part bioactive agent deliverysystem according to this invention. As shown, disposable part 8 has notyet been connected to reusable part 6. Arrows in FIG. 12 show howhousing 36 of disposable part 8 will align with housing 10 of reusablepart 6 to engage bolus chamber plunger 51 a (biased by spring 53) withbolus chamber piston 51 in bolus chamber 46, reservoir plunger 34 a(biased by spring 28) with reservoir piston 34 in reservoir 38, andvalve driver 13 with valve 50. Springs 28 and 53 compress whendisposable part 8 connects to reusable part 6, as discussed above.

FIG. 13 shows an embodiment adding components of a transdermal bioactiveagent delivery system with solvent recovery to e.g., the embodiment ofFIG. 12. Springs 28 and 53 of the reusable part are shown engagingpistons 34 and 52, respectively, of the disposable part 8. Thedisposable part 8 also includes a manifold 300, which provides the fluidpaths between the valve 50 and the reservoir 38, between the valve 50and the bolus chamber 46, and between the valve 50 and the outlet. Anoutlet path 52 leads to a fitting 320 with a fluid flow channel thatpasses through openings in the centers of a solvent recovery chamber 328(containing, e.g., a desiccant), a spacer 314 with a plurality ofopenings, and a gas-permeable membrane 310 to reach a transdermalmembrane 305. A support ring 328 provides support to the structure. Asdescribed earlier, vaporized solvent from the bioactive agent solutioncan pass from the wetted transdermal membrane 305 through gas-permeablemembrane 320 and the openings in spacer 314 to enter the solventrecovery chamber. The rate and timing of transdermal bioactive agentdelivery can be controlled, e.g., by balancing the timing and thedelivery rate of the bioactive agent solution from the bolus chamberwith the amount of desiccant in the solvent recovery chamber and/or thepermeability of the gas permeable membrane.

Transdermal patch 305 may be any appropriate material(s) or have anyappropriate characteristics that can transfer active agent across themembrane. A membrane may be hydrophilic or hydrophobic. A membrane mayhave pores (as described in more detail below), such as from 0.010-0.01um (e.g., from 0.02 um-0.05 um, etc.). A membrane may have porosity over20%-60% (e.g., from 30%-50%, from 45% to 50%, etc.). In a particularexample a polypropylene such as Celgard 2400 polypropylene (e.g., with athickness around 25 um such as between 1 um and 100 um, with a pore sizearound 0.043 such as from 0.005 to 0.2 um, etc. may be used). A materialmay be chosen based on the bioactive agent, length of treatment, etc. Apatch and bioactive agent delivery system may be configured to delivereffective membrane wetting of a skin delivery membrane. Membrane wettingrefers to the extent to which pores in a membrane are penetrated by afluid (e.g., displacing a media such as air in pores in the membranewith a fluid, in this example with bioactive agent). Effective wettingmay include how quickly a membrane is wetted, a % of wetting, etc.Effective wetting may be, for example, faster wetting which may allowfaster transfer of active agent across a skin delivery membrane.Effective wetting may be, for example, more complete wetting (e.g., agreater number or percent pores in a membrane are wetted). Effectivemembrane wetting is generally useful as it allows faster and/or morecomplete active agent fluid transfer across the membrane for delivery tothe user. Membrane wetting may occur in less than 5 seconds, less than 4seconds, less than 3 seconds, less than 2 seconds, less than 1 second,less than 0.5 seconds. Bioactive agent transfer across skin deliverymembrane 305 to/through a user's skin is facilitated by bioactive agentbeing dissolved in or otherwise transportable by a solvent. Whenmultiple doses of bioactive agent are delivered to a user over time froma single disposable part an excess amount of solvent (e.g., solvent fromeach dose) may collect (build up) in the system, e.g., in fluid space202. Excess solvent in the fluid space (or membrane) will dilutebioactive agent concentration in a subsequent dose of bioactive agentreceived into the fluid space (or membrane).

FIGS. 14A-14D and FIGS. 15A-E show an embodiment of a disposable partthat can be used along with a reusable part to transdermally deliver abioactive agent. As in the embodiments described above, the disposablepart houses the bioactive agent reservoir, bolus chamber and valve. Thedisposable part receives a force from a reusable part to pressurize thebioactive agent, and the reusable part controls movement of the valve todeliver the bioactive agent to a transdermal membrane.

FIGS. 15A-B show manifold 680 of disposable part 608 for holding andfluidly connecting reservoir 638, valve 650, and dosing or bolus chamber646. Valve 650 is a three-way valve having a movable valve core 674 asdescribed above. As described above, valve core 650 can be in a firstposition or a second position. When valve 650 is in a first position, aflow path open between bolus chamber 646 and the system outlet (and tothe transdermal patch and user); the flow path is closed betweenreservoir 638 and bolus chamber 646. When valve 650 is in a secondposition, a flow path between reservoir 638 and dosing or bolus chamber646 is open, and the flow path is closed between bolus chamber 646 andthe outlet is closed. As described above, there is no direct pathway forbioactive agent flow from reservoir 638 to the outlet, minimizing therisk of unintentional bioactive agent flow or overdose. The housing 636of the disposable part 608 is also shown. FIG. 15B is an exploded viewof disposable part 608 showing the reservoir 638, reservoir piston 634,bolus chamber 646, bolus chamber piston 651, valve core 674 and manifold680. FIG. 15B also shows the transdermal membrane and solvent recoveryelements at the system outlet (described in more detail with respect toFIGS. 14A-D).

FIGS. 15C-E show different views of manifold 680. Manifold includesvalve body 676 configured to receive valve core 674, end cap 690 forcapping reservoir 638 and end cap 691 for capping bolus chamber 646.Manifold 680 also includes first side port 695 and second side port 696which may be useful for delivering (loading) bioactive agent toreservoir 638 and bolus chamber 646, respectively, through fluid ventsin the end caps, such as fluid vent 692. (In some variations, a manifoldmay have zero, one, two or more than two loading ports). FIG. 15E showsan air vent 694 of valve 50 that can be used to bleed air from thesystem during manufacturing.

FIGS. 14A-14D show exploded views of an embodiment of a transdermalmembrane and solvent recovery system for use at the outlet of thebioactive agent delivery system, such as a two-part bioactive agentdelivery system along the lines discussed above with respect of FIG. 15.FIGS. 14A and 14C show exploded top views, and FIG. 14B shows anexploded bottom view. FIGS. 14C and 14D show one example of how thetransdermal patch shown in FIGS. 14A-14B can be assembled.

In this embodiment, transdermal membrane and solvent recovery system 500includes a backing 528 covering an absorbent or desiccant 522 within achamber 521 formed by a ridge 520 in support structure 514. Openings 516in support structure 514 communicate with a gas permeable membrane 510covering a transdermal membrane 505. The outlet of the valve 650described above with respect to FIG. 15 communicates with opening 626 insupport structure 514 to deliver a solution of bioactive agent totransdermal membrane 505. Solvent from the bioactive agent solution mayevaporate and pass through gas-permeable membrane 510 to be absorbed byabsorbent or desiccant 522.

FIGS. 14C and 14D show how transdermal membrane 500 can be assembled.Gas permeable member 510 is layered between transdermal membrane 505 andattached to support structure 514. Part or essentially all of gaspermeable member 510 may be attached to support structure 514. Edge 518of support structure 514 is attached to (sealed with) edge 506 oftransdermal membrane 505 to enclose or contain gas permeable membrane510. First step 550 shows gas permeable membrane 510 placed over thecentral portion of the top side of support structure 514. Gas permeablemembrane 510 is attached to support structure 514 such as by ultrasonicwelding or another appropriate method. Second step 552 shows transdermalmembrane 505 placed over gas permeable membrane 510 on support structure514, and connected to support structure 514 at its edges such as by heatand ultrasonic welding or another appropriate method. Third step 554shows the bottom side of support structure 514 with chamber 521surrounded by rim 520. Fourth step 556 shows absorbent 522 placed inchamber 521. Fifth step 558 shows backing 528 placed over absorbent onsupport structure 514. Backing 528 is attached to support structure 514at rim 520 such as by ultrasonic welding or another appropriate method.Although shown as generally rectangular with rounded edges, transdermalmembrane and solvent recovery element 500 and any other transdermalpatches described herein or used with a bioactive delivery system asdescribed herein for delivering bioactive agent to a user may have anyshape able to deliver bioactive agent to a user, such as circular,ellipsoid, rectangular, round, rounded square, square, triangular, etc.

FIGS. 16A-B show another embodiment of the disposable part component ofa two-part bioactive agent delivery system similar to that of FIG. 15but with the bolus chamber 646 formed as a separate element, as shownbest in the exploded view of FIG. 16B.

FIGS. 17A-17E show another embodiment of a disposable part for use witha two-part transdermal bioactive agent delivery system. Similar to theembodiments of FIGS. 14, 15 and 16, the disposable part houses thebioactive agent reservoir, bolus chamber and valve. The disposable partreceives a force from a reusable part to pressurize the bioactive agent,and the reusable part controls movement of the valve to deliver thebioactive agent to a transdermal membrane.

FIGS. 17A-B show reservoir 838, valve 850, valve core 876 (shown insideof valve body 850), and bolus chamber 846. Reservoir 838 includes piston834 for pressurizing bioactive agent in the reservoir when a force isexerted on piston 834 by a reusable part of the two-part system. In thisembodiment, the spring 882 biasing the bolus chamber piston 851 is inthe disposable part, and it compresses when pressurized bioactive agentfrom the reservoir enters the bolus chamber. When valve core 876 isturned by the reusable part, valve 850 alternately connects reservoir838 with bolus chamber 846 and bolus chamber 846 with a transdermalmembrane, but it prevents a direct flow path between reservoir 838 andthe transdermal membrane to reduce the risk of unintentional bioactiveagent flow or overdose to a user. FIG. 17B also shows a housing 836 forhousing these elements.

As shown in FIGS. 17C-E, the flow paths among the reservoir 838, valve850 and bolus chamber 846 are formed in a structural support member 814.The outlet 848 of reservoir 838 leads to an opening 886 in thestructural support member 814, and opening 886 leads to a flow path 888formed in the support member 814. A seal 820 covers the opening 886 andflow path 888. Pressurized bioactive agent in flow path 888 movesthrough opening 884 and valve port 896 to enter the valve when thereusable part turns the valve core to the appropriate position. When thereusable part turns the valve core to its other position, pressurizedbioactive agent exits the bolus chamber through valve port 895 andopening 885 in structural support member 814 to reach transdermalmembrane 805.

In this embodiment, the system includes a solvent recovery system with abacking 830 covering an absorbent or desiccant 822 within a chamber 821formed by a ridge 819 in support structure 814. Openings 816 in supportstructure 814 communicate with a gas permeable membrane 810 coveringtransdermal membrane 805. Solvent from the bioactive agent solution mayevaporate and pass through gas-permeable membrane 810 to be absorbed byabsorbent or desiccant 822.

The configuration shown in FIGS. 17A-E may have relatively simple partsfor manufacture (such as by molding parts for assembly). Such aconfiguration may minimize the lengths of one or more flow paths and mayminimize the amount of space contained in the flow path. A flow pathlength between a valve, outlet and/or delivery component such as betweena bolus chamber, valve, or outlet and an outlet, delivery component,transdermal patch, fluid space of a transdermal patch, or skin deliverymember of a transdermal patch may be configured to hold less than 5 μl,less than 4 μl, less than 3 μl, less than 2 μl, or less than 1 μl offluid media. A relatively shorter flow path length from the boluschamber to the outlet and skin delivery member may minimize the time foractive agent to move from the bolus chamber to the outlet (or skindelivery member). For example, such amounts of air or other gas presentin a flow path may decrease delivery speed or increase delivery time andreduce skin delivery member wetting efficiency. As described above,rapid bioactive agent movement may be important to obtain effectivewetting.

FIGS. 18A-18C show yet another embodiment of a disposable part for usein a two-part transdermal bioactive agent delivery system. Similar tothe embodiments of FIGS. 14-17, the disposable part houses the bioactiveagent reservoir, bolus chamber and valve. The disposable part receives aforce from a reusable part to pressurize the bioactive agent, and thereusable part controls movement of the valve to deliver the bioactiveagent to a transdermal membrane. In this embodiment, the bolus chamber946 and the reservoir 938 are molded as a single part.

FIGS. 18A-C reservoir 938, valve 950, valve core 976 (shown inside ofvalve body 950), and bolus chamber 946. Reservoir 938 includes piston934 for pressurizing bioactive agent in the reservoir when a force isexerted on piston 934 by a reusable part of the two-part system. In thisembodiment, the spring 982 biasing the bolus chamber piston 951 is inthe disposable part, and it compresses when pressurized bioactive agentfrom the reservoir enters the bolus chamber. When valve core 976 isturned by the reusable part, valve 950 alternately connects reservoir938 with bolus chamber 946 (via valve ports 948 and 995) and boluschamber 946 with a transdermal membrane beneath support member 914 (viavalve ports 995 and 996 and opening 986 in structural support 914), butit prevents a direct flow path between reservoir 938 and the transdermalmembrane to reduce the risk of unintentional bioactive agent flow oroverdose to a user. Housing 936 is provided for housing these elements.

In this embodiment, the system includes a solvent recovery system 928similar to that described above with a backing covering an absorbent ordesiccant within a chamber formed by a ridge in support structure 914.

FIGS. 19A-19F show different views of still another embodiment of adisposable part for use with a two-part transdermal bioactive agentdelivery system. Similar to the embodiments of FIGS. 14-18, thedisposable part houses the bioactive agent reservoir, bolus chamber andvalve. The disposable part receives a force from a reusable part topressurize the bioactive agent, and the reusable part controls movementof the valve to deliver the bioactive agent to a transdermal membrane.In this embodiment, the valve, bolus chamber and reservoir are molded asone part 1010, the manifold and desiccant housing 1012 are molded asanother part, and the housing 1081 is the third part of the disposablepart.

FIG. 19 show reservoir 1038, valve 1050, valve core 1076 (shown insideof valve body 1050), and bolus chamber 1046. Reservoir 1038 includespiston 1034 for pressurizing bioactive agent in the reservoir when aforce is exerted on piston 1034 by a reusable part of the two-partsystem. In this embodiment, the spring (not shown) biasing the boluschamber piston 1051 is in the disposable part, and it compresses whenpressurized bioactive agent from the reservoir enters the bolus chamber.When valve core 1076 is turned by the reusable part, valve 1050alternately connects reservoir 1038 with bolus chamber 1046 and boluschamber 1046 with a transdermal membrane 1005, but it prevents a directflow path between reservoir 1038 and the transdermal membrane to reducethe risk of unintentional bioactive agent flow or overdose to a user.FIG. 19B also shows a housing 1081 for housing these elements.

As shown in FIG. 19, flow paths among the reservoir 1038, valve 1050 andbolus chamber 1046 are formed in a structural support member 1080. Theoutlet of reservoir 838 leads to openings 1084 and 1084 a in themanifold housing 1012 and structural support member 1014, respectively,and opening 1084 a leads to a flow path 1048 formed in the supportmember 1014. A seal 1020 covers the opening 1084 a and flow path 1048.Pressurized bioactive agent in flow path 1048 moves through openings1089 a and 1089 to enter the valve, exits the valve and passes throughopenings 1085 a and 1085, covered flow path 1049 and opening 1088 toenter the bolus chamber 1046 when the reusable part turns the valve coreto the appropriate position. When the reusable part turns the valve coreto its other position, pressurized bioactive agent exits the boluschamber 1046 through the valve and openings 1088 and 1086 in structuralsupport member 1014 and opening 1086 a in manifold housing 1012 to reachtransdermal membrane 1005.

This embodiment also includes a solvent recovery system. Desiccant 1022is disposed in manifold housing 1012. An opening 1024 in desiccant 1022communicates openings 1085 with 1085 a and 1086 with 1086 a. Openings1016 in support structure 1014 communicate with a gas permeable membrane1010 covering transdermal membrane 1005. Solvent from the bioactiveagent solution may evaporate and pass through gas-permeable membrane1010 to be absorbed by desiccant 1022.

FIGS. 20A-20E show different views of a two-part bioactive agentdelivery system 1102 with disposable part 1108 connectable with reusablepart 1106. System 1102 has a user interface 1122, such as for receivinga user's command or displaying a system parameter.

FIG. 20B shows a perspective view of disposable part 1108 being placedinto reusable part 1106 to form the active agent delivery system shownin FIG. 20A. Disposable part 1108 has a housing 1110 and a transdermalmembrane or patch (not shown) beneath the patch area 1100 of base 1101.Reusable part 1106 includes spring 1128 for pressurizing the reservoir1138 in the disposable part and a spring 1112 for providing a force tothe bolus chamber 1146 in disposable part 1108. Springs 1112 and 1128are compressed and loaded when reusable part 1106 is connected todisposable part 1108.

FIG. 20C also shows that valve driver 1113 in reusable part 1106 isinserted into valve 1150 when reusable part 1106 is connected todisposable part 1108. Valve driver 1113 controls the configuration ofvalve 1150 to control bioactive agent flow from reservoir 1138 to boluschamber 1146, and from bolus chamber 1146 to transdermal patch 1100.

FIG. 20D shows reservoir 1138 filled with bioactive agent. Spring 1128is compressed and provides a force to piston 1134 of reservoir 1138 topressurize bioactive agent within the reservoir. FIG. 20D also shows adose of bioactive agent in bolus chamber 1146. Spring 1112 is compressedagainst housing 1110 in reusable part and provides a force againstpiston 1151 to maintain pressure on the bioactive agent in the boluschamber.

FIG. 20E shows a spent bioactive agent delivery system 1102 withoutbioactive agent, such as after system use by a user. Reservoir 1138 isessentially devoid of bioactive agent, and piston 1135 is at the bottomof the reservoir under the force of spring 1128. Bolus chamber 1146 isalso essentially devoid of bioactive agent, and piston 1151 is at thebottom of the chamber by the force of spring 1112. (A minimal volume,such as a dead volume, of bioactive agent, may be left behind, in thereservoir and/or bolus chamber.).

FIGS. 20D-20E also show valve driver 1113 powered by battery 1114 forchanging the configuration of valve 1150. The components shown in FIGS.20A-E may also or instead by used in another system, such as the systemshown in FIGS. 11A-C.

FIGS. 21A-21F show another embodiment of a two-part bioactive agentdelivery system 1202, such as a wearable system, for transdermaldelivery of a bioactive agent. In this embodiment, the location of thetransdermal patch is offset from the center to minimize the overallsystem thickness of the system. FIG. 21A shows a perspective view of anassembled active agent delivery system with a reusable part 1206 and adisposable part 1208. FIG. 21B shows a perspective view of active agentdelivery system separated into reusable part 1206 and a disposable part1208 ready for assembly. Disposable part 1208 is shown partiallycutaway. Transdermal patch 1208 is offset from the center to allowadditional room for the reservoir and bolus chamber. FIG. 21C shows acutaway perspective view of the system shown in FIG. 21A (system inrotated 180°). FIG. 21D shows another cutaway perspective view of thesystem shown in FIG. 21A in the same orientation as in FIG. 21C.

System 1202 includes reusable part 1206 and disposable part 1208 withtransdermal membrane or patch (not shown) beneath patch area 1200 ofbase 1201. Valve 1250 and valve driver 1213 have a relatively shorterprofile than do the reservoir and bolus chamber and overlie patch area1200. Reservoir 1238 and 1246 are coaxial and have a relatively higherprofile than do valve 1250 and valve driver 1213. Reservoir 1238 may beconfigured to hold a convenient amount of bioactive agent, such as from500 μl to 1500 μl of bioactive agent (e.g., from 500 μl to 800 μl, 400μl to 700 μl, etc. or any of the amounts listed elsewhere herein).

Battery 1214 may be a coin cell or other power source that requiresrelatively minimal space in order to maintain an overall desired systemprofile. A desired system profile may be a relatively low profile, forexample such a system (or any system as described herein) may beconfigured to be between 10 mm to 30 mm in thickness (e.g., in height)such as at least 10.0 mm, 11.0 mm, 12.0 mm, 13.0 mm, 14.0 mm, 15.0 mm,16.0 mm, or less than 20.0 mm, 19.0 mm, 18.0 mm, 17.0 mm, 16.0 mm, 15.0mm, 14.0 mm, 13.0 mm or any values in between these values, such from12.0 mm to 15.0 mm, 14.0 mm to 16.0 mm, 14.5 mm to 16.0 mm, etc.

For example, such a system (or any system as described herein) may beconfigured to be between 10 mm and 80 mm in width and/or length. Forexample, a system may be at 10 mm, 20 mm, 30 mm, 40 mm, 50 mm, 60 mm, 70mm, 80 mm, 90 mm or less than 100 mm, 90 mm, 80, mm, 70 mm, 60 mm, 50mm, 40 mm, 30 mm, 20 mm, etc. on in between any of these amounts. Insome variations, a system may be configured to be a wearable system witha height between 13.0 mm and 16.0 mm, and a width between 30 mm and 50mm (such as 34 mm×48 mm, 37 mm×37 mm, etc.).

FIG. 21E shows reservoir 1238 filled with bioactive agent. Spring 1228is compressed and provides a force against piston 1234 to pressurizereservoir 1238. FIG. 21E also shows a dose of bioactive agent in boluschamber 1246. Spring 1212 is compressed as bolus chamber 1246 fills withpressurized bioactive agent, moving piston 1251 against the action ofspring 1212. FIG. 21F shows a spent bioactive agent delivery system 1202without bioactive agent, such as after system use by a user. Reservoir1238 is essentially devoid of bioactive agent, and piston 1246 is at thebottom of reservoir 1238 under action of spring 1228. Bolus chamber 1246is also essentially devoid of bioactive agent, and piston 1251 is at thebottom of bolus chamber 1246 under the action of spring 1212 (A minimalvolume, such as a dead volume, of bioactive agent, may be left behind ineither or both the reservoir and the bolus chamber.).

FIGS. 22A-22D show embodiments of a valve and valve driver forconnecting a valve driver (such as in a reusable part as describedherein) with a valve core (such as in a disposable part as describedherein) to rotate the valve core to control bioactive agent flow betweenthe reservoir and bolus chamber and bolus chamber and outlet (e.g., to atransdermal patch or user). Valve driver 1313 includes shaft 1315 with ataper configured to fit with a corresponding tapered hole 1378 in valvecore 1376. In some variations, a shaft may have a rib 1321 or aplurality of ribs (e.g., at least 2, at least 3, at least 4, at least 5,at least 6, etc.) that may help hold the shaft in the hole, as shown inFIG. 22D. A valve core may be made from a softer material than is therib(s) and the rib(s) may crush when the shaft is inserted into thehole.

FIG. 23 shows another embodiment of a bioactive agent delivery system1402. Bioactive agent delivery system 1402 includes damping mechanism1412 configured to prevent all of the force from the spring(s) in thesystem from unloading (suddenly) onto the user. FIG. 23 also showsbioactive agent delivery system 1402 with housing 10 sufficiently strongto withstand force from the springs. FIG. 23 also shows clips 1416configured to hold the reusable part and disposable part together. FIG.23 also shows flex region 1414 configured to flex upon pressure andrelease clips 1416 to release disposable part 1408 from reusable part1106. Such clips or other attachment mechanisms can be used with any ofthe two-part delivery system embodiments discussed herein.

FIGS. 24A-24B show embodiments of a bioactive agent delivery system withmechanisms to prevent sudden release of spring force onto a user. FIG.24A shows bioactive agent delivery system 1502 with reusable part 1506and disposable part 1508 with mechanism 1510 for preventing the suddenrelease of spring force. In FIG. 24A the system is held together byclips, and a passive mechanism 1510 is present in the system (e.g.,during system use). As shown by the arrow indicating a change in devicestate from connected to disconnected, mechanism 1510 prevents fullrelease of disposable part 1508. A user secondary clip is released bythe user to fully remove disposable part 1508 from reusable part 1506.

In FIG. 24B a system 1552 is held together by clips, and a passivemechanism 1550 is present in the system (e.g., during system use). Asshown by the arrow indicating a change in device state from connected todisconnected, passive mechanism 1550 prevents full release of disposablepart 1558. A twist to the system (e.g., by a user) fully removesdisposable part 1558 from reusable part 1556.

FIG. 25 shows yet another embodiment of a bioactive agent deliverysystem with a reusable part 1606 and a disposable part 1608. As inearlier embodiments, the disposable part 1608 has a reservoir 1638containing a bioactive agent and a bolus chamber 1646 communicable withreservoir 1638 through a valve 1650. In this embodiment, bolus chamberspring 1612 extends between a surface in the disposable part and asurface of a movable actuator 1635 to apply a force to bolus chamberpiston 1651. Likewise, reservoir spring 1628 extends between a surfacein the disposable part and a surface of a movable actuator 1652 to applya force to reservoir piston 1634. The valve actuator 1613 is alsodisposed within disposable part 1608. When the disposable part 1608 isattached to the reusable part 1606 (by, e.g., sliding rails 1696 intocorresponding grooves 1698 and tightening screws 1697), an electricalplug 1615 in the disposable part goes into a corresponding socket (notshown) in a controller and power supply 1690 in the reusable part. Valve1650 can then be actuated by providing power to valve actuator 1613 toturn valve 1650 to allow bioactive agent to move from reservoir 1638 tobolus chamber 1646 or from bolus chamber 1646 to the patient (e.g.,through a transdermal membrane) in the manner described above. Also asdescribed above, the reusable part 1606 contains a display and otherelectronics 1622.

FIGS. 26-28 show yet another embodiment of a bioactive agent deliverysystem with a reusable part 1706 and a disposable part 1708. Thereusable part 1706 snaps onto the disposable part 1708 via snapconnections (not shown). Release buttons 1730 on the exterior of housing1902 may be depressed to disconnect the reusable part 1706 from thedisposable part 1708. User actuatable buttons 1724, 1726 and 1728 may beused to provide input to the device. A transparent display portion 1722of the housing 1902 permits the device's display to be seen.

As shown in FIGS. 28A-C, the reusable part 1706 has an upper housing1902 and a lower housing 1904. Wire pairs 1932 and bendable metalcomponents 1940 connect buttons 1726 and 1728 to the printed circuitboard 1942. Button 1724 moves the cantilever 1725 formed in housing 1902into contact with a switch on the PCB 1942. An adhesive member 1936attaches the display 1938 to the housing.

A battery 1950 and battery spacer 1948 rest in a lower housing 1904. Thebattery 1950 power a valve motor 1956. Valve motor 1956 connects to thevalve in the reusable part view couplers 1958 and 1960. Springs 1952 and1954 connect to the bolus chamber 1803 and reservoir 1801, respectively,of the disposable part 1708 (shown in FIG. 28D). A movable contactswitch 1962 moves inward when the reusable part 1706 is connected to thedisposable part 1708 to depress a switch on the PCB 1942 to indicatethat the two components have been connected.

FIGS. 28D-F show aspects of the disposable part 1708. Housing 1737 hascompartments 1738 and 1746 containing the reservoir 1801 and boluschamber 1803. Pistons 1802 and 1804 are disposed in the reservoir 1801and bolus chamber 1803, respectively, and interact with springs 1954 and1952, respectively, when the disposable part is connected to thereusable part. Housing 1737 also contains the valve housing 1745 andvalve core 1806. Valve core connects to valve motor 1956 via couplers1958 and 1960 (FIG. 28C) when the reusable part is connected to thedisposable part.

Attached below housing 1737 is a membrane chassis 1809. Absorbentmaterial, such as absorbent paper 1808, sits in a tray 1810 disposed inthe top side of chassis 1809. A plurality of openings 1813 in tray 1810extend through chassis 1809. Beneath the chassis 1809 are a transdermalmembrane 1811 (such as, e.g., a polypropylene membrane, as describedbelow) and a gas permeable membrane 1812 having pores size to permitgaseous solvent to pass through, as described elsewhere in thisdisclosure. A fluid passageway 1807 extends up from chassis 1809 intovalve housing 1745 when chassis 1809 is attached to the underside ofhousing 1737 to provide a fluid flow path from valve core 1806 through anotch 1814 in gas permeable membrane 1812 to transdermal membrane 1811.In some embodiments, the outer perimeter of transdermal membrane 1811 isheat bonded to the bottom of chassis 1809, which holds the gas permeablemembrane 1812 in place as well.

A device adhesive layer 1816 with double-sided adhesive attaches themembrane chassis 1809 to a skin adhesive layer 1739 formed, e.g., fromfoamed tape. Openings 1817 and 1818 in the device adhesive layer 1816and skin adhesive layer 1739, respectively, expose the underside oftransdermal membrane 1811, as shown in FIG. 28F, in which the releaseliner 1740 is shown to be transparent in order to view the layers aboveit. A removable release liner 1740 covers the adhesive side of skinadhesive layer 1739 and the exposed portion of transdermal membrane 1811until the device is ready to be adhesively attached to a user's skin totransdermally deliver nicotine or other bioactive agent to the user.

In use, when the reusable part 1706 is connected to the disposable part1708, switch 1962 moves to indicate to the device's microcontroller thatthe two pieces have been connected. A microcontroller and memory on thePCB 1942 logs the time of connection. In some embodiments, the PCBincludes a wireless transmitter (using, e.g., the Bluetoothcommunication protocol) for communicating the fact and timing ofconnection to a remote device, such as a smart phone running amonitoring application. This information may also be sent to a remotelocation for monitoring daily compliance by a user. Connecting the twocomponents also compresses springs 1954 and 1952 against pistons 1802and 1804, respectively, to pressurize the contents of the reservoir 1801and bolus chamber 1803, such as a solution of bioactive agent (e.g.,nicotine) and solvent (e.g., alcohol).

Release lining 1740 may then be removed to expose the skin adhesivebeneath skin adhesive layer 1739 and the underside of the transdermalmembrane 1811. The combined device 1706 and 1708 is then attached to anexposed portion of the user's skin. The valve motor 1956 turns the valvecore 1806 under the control of the device's microprocessor to deliverthe contents of bolus chamber 1803 through passageway 1807 totransdermal membrane 1811. As the bioactive agent passes throughtransdermal membrane 1811 to the user's skin, solvent evaporates fromthe bioactive agent solution, passes through gas permeable membrane 1812and openings 1813 into the absorbent material 1808. Removing solventvapor during delivery of bioactive agent helps the device control thedelivery profile of the bioactive agent, as described, e.g., in U.S.Pat. Nos. 8,252,321; 8,440,221; and 7,780,981.

Buttons 1726 and 1728 may be used to set program timing for delivery ofthe bioactive agent. For example, when delivering nicotine in a nicotinereplacement therapy protocol, the user may program in a wake time sothat a bolus of nicotine can be delivered before the user awakes. Thesebuttons may also be used to toggle through screens, set up Bluetoothconnections with remote devices, turn the display on and off, etc.

Button 1724 can be depressed by the user to indicate a craving, such asa craving for a cigarette. The system controller logs actuation of thecrave button 1724 and sends craving information via the wirelesstransmitter to a remote device (such as a smart phone). An applicationon the remote device can then coach the user through the cravingexperience, display historical craving data, etc. Craving informationfrom multiple users can be aggregated at a central location (e.g., overthe internet via WiFi or a cellular network) to help refine dosage andusage patterns. Support information can also be sent back to the user'ssmartphone application, such as a text message saying, “We received yourcraving indication. Concentrate on breathing deeply for 30 seconds untilcraving passes.” More details of the psychological support that can beprovided through the device may be found in US 2014/0207048.

The device can also note and log when a first bolus of nicotine or otheractive compound is delivered. In that way, the device can generate anotice to replace the disposable part a set time after the first bolushas been delivered. This information and other information about theoperation of the device (e.g., self-test results) can be sent to aremote device (such as a smart phone) via the device's wirelesstransmitter.

FIG. 29 illustrates an embodiment of a transdermal delivery deviceincluding a reusable part 2006 with a control unit and a disposable part2008. As an alternative to the switch 1962 to show a connection betweenthe reusable part and the disposable part, this embodiment employsconductive elements on the exterior of the two housings to close acircuit, which sends a signal to the device electronics that the twocomponents have been connected. In the illustrated embodiment, thereusable part 2006 includes a conductive elastomer 2007, and thedisposable part 2008 includes a conductive elastomer 2009. Theconductive elastomer 2007 and conductive elastomer 2009 complete anelectrical connection when the reusable part 2006 and disposable part2008 are engaged with each other.

A bioactive agent delivery system as described herein may be useful fordelivering a bioactive agent to any part on or in a user's body. In someparticular variations, a bioactive agent delivery system as describedherein may deliver a bioactive agent topically or transdermally to orthrough a user's skin. For example a bioactive agent delivery system maybe useful for delivering any type of bioactive agent to a user topicallyor transdermally or with another method, such as for deliveringalprazolam, apomorphine, azelastine, buprenorphine, bupropion,clonidine, enalpril, estradiol, ethinyl estradiol, fentanyl,granisetron, another hormone, insulin, lidocaine, memantine,methylphenidate, methamphetamine, nitroglycerine, nicotine,norethisterone acetate (NETA), norelgestromine, oxybutynin, another painmanagement agent, pergolide, phenteramine, pramipexole, ramipril,ropinirole, rotifotine, scopolamine, selegiline, tecrine, testosterone,timolol, tolterodine, etc. Transdermal delivery may be especially usefulfor small lipids or oil-soluble substances. In some variations, abioactive agent may penetrate (e.g., move across) skin on its own(passive diffusion). The skin provides a strong barrier against materialtransfer (such as bioactive agent penetration) however, and manybioactive agents penetrate the skin very poorly. In some variations,topical or transdermal transfer of a bioactive agent may be enhanced. Insome examples, movement of a bioactive agent across skin may be enhancedby a chemical enhancer such as, for example, using ethosomes(phospholipid-based elastic nanovesicles containing a high ethanolcontent (e.g., 20-45%), liposomes, niosomes (non-ionic surfactantvesicles), a pro-drug, solid lipid nanoparticles, supersaturation (suchas by decreasing or increasing bioactive agent and/or solvent pressure,temperature, volume, etc.), transferosome (e.g., an elastic ordeformable vesicles). In some examples, movement of a bioactive agentacross skin (or otherwise into a body) may be enhanced by a physicalenhancer, such as, for example, using acoustical methods,electrophoresis, electroporation, heat assisted delivery, iontophoresis,light or another electromagnetic enhancer, magnetophoresis,microneedles, nanoporation, needle-free injection, piezoelectric dropletjet dispersion, a pump short-duration shock wave, sonophoresis, skinabrasion, another subcutaneous delivery method, thermal droplet jetdispersion, ultrasound (low-frequency ultrasound), etc. In someexamples, insulin or nicotine is delivered, such as using a transdermalpatch for nicotine delivery or a pump for insulin delivery. A needle ormicroneedle may be configured to penetrate a person's skin to any depthto deliver a bioactive agent, but in general a microneedle may beespecially useful for penetrating a top layer of a person's skinsufficient to get past the skin barrier function, but not so deep as toreach nerve endings and cause pain. A needle or microneedle(s) may besolid or non-solid, and may be hollow or contain pores or holes. Apatient contact portion may include a single needle or microneedle or aplurality of needles or microneedles such as 2 or more, 5 or more, 10 ormore, 20 or more, 50 or more, 100 or more 500 or more or any number inbetween these. The needles or microneedles may be contained in an arraymeasuring less than 5 cm×5 cm, less than 1 cm×1 cm, less than 500 mm×500mm, less than 100 mm×100 mm. a bioactive agent may flow or move aroundan outside of a microneedle or may flow or move through the inside of amicroneedle. A needle or microneedle may have (e.g., contain or becoated with) or not have an initial dose of a bioactive agent and a doseor subsequent dose may be supplied to the needle or microneedle by abioactive agent delivery device as described herein. A microneedle mayfor example, be generally tapered and may have a bevel, sharp end, ortaper at a delivery end configured for penetrating a body tissue such asan outer layer of skin. A microneedle may be less than 250 μm at itsbase, less than 450 μm height, have an opening less than 80 μm down toless than 10 μm or less than 1 μm. A pitch of a needle center to needlecenter may be less than 400 μm. A microneedle that is relatively largerin one or more of its dimensions may reduce clogging and improve fluid(bioactive agent) flow. A smaller needle may smaller than amicroorganism (such as a bacterium) to prevent (or reduce the likelihoodof) a microbiological infection. A microneedle may be used for anybioactive agent delivery but may be especially useful for delivering adrug, a genetic material, a peptide, a protein, a vaccine, etc. thatdoes not readily diffuse or penetrate through an outer skin layer.

In general bioactive agent delivery as described herein includesdelivery of a bolus (dose) of a bioactive agent from a delivery deviceto a person. Delivery from a delivery device may be pre-set(predetermined) or may be on-demand. Pre-set delivery may bepre-programmed into a delivery device or may be user-controllable.Bioactive agent delivery may be made at regular times (intervals), suchas multiple times during a day or at the same time of day but ondifferent days (periodic). Bioactive agent delivery may be pre-set butconnected to a regularly occurring temporal event such as at a certaintime every day, every week, on a particular day, every month, etc. Sucha temporal event may happen at the same time every day or may happen atdifferent times. For example, bioactive agent delivery may be based on(connected to) an alarm or to an event such as to an event on acalendar. Bioactive agent delivery in response to an alarm configured towake a person from sleep may be especially useful for delivering abioactive agent for an event that correlates with a person's dailyschedule or daily biorhythms and to a person waking up. For example,heart attacks, migraine headaches, nicotine cravings, strokes and otherevents commonly occur in the morning. Some of these have been correlatedwith biological changes (endocrine or hormonal changes) in going fromsleeping to being awake. Strokes have been shown to occur morefrequently on Mondays than any other day of the week and also to occurmore commonly in the winter. Some women experience migraine headachesthat correlate with their menstrual cycle, which are referred to as“menstrual migraines” and are thought to be related to the normal(predictable) drop in the levels of estrogen during the woman's monthlymenstrual cycle. In a particular example, a bioactive agent may be anicotine cessation substance and a delivery device may be configured todeliver the substance before an alarm wakes the person from sleep (or todeliver the bioactive agent before the time the person generallyawakens). An alarm may be set at the same time(s) on two or more days(such as consecutive, weekly, monthly, etc.) or may be set at differenttimes.

A delivery profile or delivery device may be configured to deliver arelatively constant amount of a bioactive agent to an individual or todeliver varying amounts. In some variations, a delivery profile may beconfigured to provide a relatively constant level of bioactive agent inthe bloodstream. For example, delivery may be pulsatile or overintervals and may be controlled by a rate of the transdermal patchdiffusion. In other variations, a bioactive agent delivery profile maybe configured to provide varying levels of bioactive agent in the bloodstream. For example, nicotine cravings come and go based on variousfactors, such as the time of day, food intake, the person's activities,and so on. Cravings are often greater in the morning or after dinner.Nicotine cravings are generally not a problem while the person issleeping; however they may be a problem as soon as the person wakes up.Thus, a user may benefit from having a smoking cessation agent deliveredwhen it is needed (e.g., shortly before or shortly after waking up) tominimize or prevent an expected craving and not having it delivered atother times (e.g., in the middle of the night). For example, pain can besevere during the night, and thus providing bioactive agent to managepain during the night may be helpful. A bioactive agent delivery systemas described herein may provide such an agent when it is needed (e.g.,at night as well as during the day). Providing a bioactive agent onlywhen it is needed may reduce drug metabolic load in the liver forprocessing the bioactive agent, may prevent tolerance to a bioactiveagent from building up, and so on. Bioactive agent delivery may also orinstead be continuous such as at a continuous but relatively low level.For example, a transdermal delivery apparatus or other deliveryapparatus may be configured to transfer bioactive agent to a user over aperiod of time (e.g., an hour, two hours, four hours, etc.).

As indicated elsewhere, a reusable part of an active agent deliverysystem is generally configured to work with a plurality of disposableparts and a single reusable part can be used by a user with a pluralityof disposable parts (e.g., first, second, third, etc.) over time todeliver multiple doses of a bioactive agent to the user at differenttimes or different days over weeks or months of time. Such disposableparts may be substantially the same as each other or may be differentfrom each other. For example, two or more disposable parts for use witha single reusable part may have the same configuration as each other ormay have different configurations as long as they can work with thereusable part. Two or more disposable parts configured to work with a(the same) reusable part may contain the same active agent or differentactive agents (or may contain the same active agent but at differentconcentrations). Additionally, a single disposable part may beconfigured to work with a plurality of differently configured reusableparts. For example, different reusable parts may have different powersources (batteries, etc.), different user interfaces, differentconfigurations, etc. but may still be configured to work with the (same)disposable part.

Any of the components described herein can also or instead be used withother components in addition to or instead of the components shown inorder to delivery bioactive agent to a user. For example, any of thetransdermal patches described herein can be used with another disposablepart or a different bioactive agent delivery system, etc. In somevariations, a transdermal delivery apparatus could be separate from adisposable part. In some examples, a transdermal delivery apparatuscould be used with an entirely different bioactive agent deliverysystem. In some variations, a bioactive agent delivery system asdescribed herein may not be readily separable into two or more pieces.Rather, it may be configured as a single apparatus and not have aseparate (or readily separable) reusable part and disposable part. Insome variations, a component(s) as described herein as being part of areusable part (or part a disposable part) may instead be in thedisposable part (or a reusable part). For example, a power source (e.g.,battery) may be in a disposable part rather than in a reusable part.This may be helpful, for example, for supplying a fresh power source(battery) with a disposable part when a new (replacement) disposablepart is placed on a reusable part. In some variations, an active agentdelivery system may have a plurality of disposable or a plurality ofreusable parts that work together but the parts may be configured to beseparately placed on a reusable part. For example, a power source (e.g.,battery) or other component may be separately removable and replaceablewith a fresh power source (e.g., battery) and both a disposable part anda power source may be separately replaceable (e.g., as two separatedisposable parts) on a reusable part.

In some variations, a disposable part may be configured to be recharged.For examples, a disposable part may be refillable with an additionalquantity of bioactive agent and may be reusable. A disposable part maybe refilled with an additional quantity of bioactive agent while inplace on a reusable part or may be removed from a reusable part,refilled with an additional quantity of bioactive agent, and placed backinto the reusable part (e.g., replaced). Refilling a disposable part maybe useful, for example, for keeping a wearable active agent systemrelatively small by minimizing the amount of active agent in the systemat any one time. The systems, devices and methods as described hereinmay be used for or configured to be used for delivering a bioactiveagent to any user, such as a person, an animal, a domesticated animal, awild animal, a cat, a cow, a dog, a horse, a swine, etc.

In some embodiments the solvent solution includes water, alcohol, and adrug or bioactive agent. In some embodiments the alcohol can be one ormore of isopropanol, ethanol, and methanol. The solvent solution canalso include one or more of a: surfactant, excipient, or other componentintended to enhance permeation or decrease skin sensitivity or skinreaction.

The solvent solution can have a ratio of water to alcohol of about 40:60to about 60:40. The solvent solution can have a ratio of water toalcohol of about 45:55 to about 55:45. The solvent solution can have aratio of water to alcohol of about 46:54 to about 54:46. The solventsolution can have a ratio of water to alcohol of about 47:53 to about53:47. The solvent solution can have a ratio of water to alcohol ofabout 48:52 to about 52:48. The solvent solution can have a ratio ofwater to alcohol of about 49:51 to about 51:49.

A variety of different drugs or bioactive agents can be used with thesystems described herein. In some embodiments the bioactive agentincludes nicotine. For example, nicotine can be present in the solventsolution from about 0.5% to about 20% by volume. In some embodimentsnicotine can be present in the solvent solution from about 0.5% to about10% by volume. In some embodiments nicotine can be present in thesolvent solution from about 0.5% to about 5% by volume. In someembodiments nicotine can be present in the solvent solution from about0.5% to about 3% by volume.

Other examples of bioactive agents include: Acamprosate, Acetaminophen,Acetaminophen+Oxycodone, Alevicyn SG, Alfentanil, Allopurinol,Almotriptan, Alprazolam, Alprazolam XR, Amitriptylinem, Amoxapine,Apomorphine, Aripiprazole, Armodafinil, Asenapine maleate, Atomoxetine,Azelastine HCL, Baclofen, Benzbromarone, Benzydamine, Brexpiprazole,Budesonide, Bupivacaine, Buprenorphine, Buprenorphine+Nalaxone,Bupropion, Bupropion Hydrobromide, Bupropion Hydrochloride, BupropionSR, Bupropion XR, Buspirone, Cabergoline, Capsaicin, Carbamazepine CR,Carbamazepine XR, Carbidopa+Levodopa Er, Carisprodol, Celecoxib,Citalopram, Clobazam, Clonazepam, Clonidine Patch, Clonidine SR,Clopidogrel, Colchicine, Cyclobenzaprine ER, Cyclobenzaprine PO,Dalteparin sodium, Desvenlafaxine, Desvenlafaxine ER, Dexamfetamine,Dexmethylphenidate Hcl, Dexmethylphenidate Hcl LA, Diazepam,Diclofenacm, Diclofenac Gel, Diclofenac IR, Diclofenac IV, DiclofenacPotassium IR, Diclofenac Potassium XR, Diclofenac Transdermal,Disulfiram, Divalproex Sodium, Dolasetron Mesilate, Doxepin, Dronabinol,Droxidopa, Duloxetine, Eletriptan, Entacapone, Escitalopram oxalate,Eslicarbazepine Acetate, Esomeprazole/naproxen, Estradiol, Estrogen,Eszopiclone, Ethosuximide, Etodolac, Ezogabine, Febuxostat, Felbamate,Fenbufen, Fentanyl Citrate, Fentanyl Oral, Fentanyl Patch, Fentanyl SL,Flunisolide, Fluorouracil, Fluoxetine, Fluticasone propionate,Fluvoxamine Cr, Formoterol, Fosphenytoin, Frovatriptan, Gabapentin,Gabapentin ER, Granisetron ER, Guanfacine, Hydrocodone Bitartrate CR,Hydrocodone+Acetaminophen, hydrocortisone, Hydromorphone Hcl,Hydroxyzine, Hypericum Extract, Ibuprofen, Indometacin, Ketorolac,Lacosamide, Lamotrigine, Lamotrigine CDT, Lamotrigine ODT, LamotrigineXR, Levetiracetam, Levetiracetam IR, Levetiracetam XR, Levomilnacipran,Levo salbutamol, Lidocaine Patch, Lidocaine/Tetracaine,Lisdexamfetamine, Lithium Carbonate, Lorazepam, Lorcaserin,Hydrochloride, Losartan, Loxapine, Meclizine, Meloxicam, Metaxalone,Methylphenidate, Methylphenidate Hydrochloride, Methylphenidate LA,Methylphenidate MR, Methylphenidate Patch, Milnacipran, Mirtazapine,Modafinil, Morphine, Morphine CR, Morphine ER, Nabilone, Nadolol,Naltrexone, Naproxen, Naratriptan, Nedocromil, Nefazodone,Nitroglycerin, Nitroglycerin Ointment, Olanzapine, Olanzapine IM,Olanzapine LA, Ondansetron, Ondansetron ODFS, Ondansetron ODT, Orlistat,Oxaprozin, Oxcarbazepine, Oxcarbazepine ER, Oxybutynin, Oxybutynin Gel,Oxycodone, Oxycodone+Acetaminophen, Oxycodone Hydrochloride, OxycodoneIR, Oxymorphone, Oxymorphone ER, Palonosetro, Pamidronate, Paroxetine,Paroxetine Mesylate, Perampanel, Phentermine+Topiramate, PhentermineHydrochloride, Phentolamine Mesylate, Pramipexole, Pramipexole-Er,Prasugrel, Prazepam, Prednisone, Pregabalin, Promethazine, Propofol,Quetiapine, Quetiapine Fumarate, Quetiapine Fumarate XR, Ramelteon,Rasagiline Mesylate, Remifentanil, Risperidone, Rivastigmine Tartrate,Rizatriptan, Ropinirole, Ropinirole XL, Ropivacaine, Rotigotine,Rufinamide, Salbutamol, Scopolamine, Selegiline, Selegiline ODT,Selegiline Transdermal, Sertraline, Sodium Oxybate, Strontium,Sufentanil-Ent, Sumatriptan Autoinjector, Sumatriptan Needle-free,Sumatriptan Succinate, Suvorexant, Tapentadol, Tapentadol ER,Tasimelteon, Temazepam, Testosterone, Tetracaine+Lidocaine,Theophylline, Tiagabine, Tiotropium, Tirofiban HcL, Tolcapone,Topiramate, Topiramate XR, Tramadol, Tramadol+Acetaminophen, TramadolER, Trazodone Cr, Triazolam, Trimipramine Maleate, Valproate SemisodiumER, Valproate Sodium, Venlafaxine, Venlafaxine ER, Vigabatrin,Vilazodone, Vortioxetine, Zaleplon, Zileuton, Ziprasidone, ZolmitriptanOral, Zolmitriptan ZMT, Zolpidem, Zolpidem Spray, Zolpidem Tartrate CR,Zolpidem Tartrate Low dose SL, Zolpidem Tartrate SL, norethisteroneacetate (NETA), enapril, ethinyl estradiol, insulin, memantine,methamphetamine, norelgestromine, pergolide, Ramipril, tecrine, timolol,tolterodine and Zonisamide.

The pore size and porosity of the vapor permeable membrane and thetransdermal membrane can be tailored to achieve a desired flow of drugthrough membrane and the desired solvent flow rate. The transdermalmembranes for use with the embodiments described above can be made froma material that is compatible with contact with the skin. In someembodiments the membrane that contacts the skin can comprisepolypropylene. In some embodiments the membrane that contacts the skincan comprise polytetrafluoroethylene (PTFE). In some embodiments themembrane that contacts the skin can comprise ethylene vinyl acetate(EVA). In some embodiments the membrane that contacts the skin cancomprise polyester and/or fluoropolymer coated polyester films. In someembodiments the membrane that contacts the skin can comprise anethylene-vinyl acetate copolymer membrane. In some embodiments themembrane that contacts the skin can comprise an ethylene vinyl acetatecopolymer (EVAC). In some embodiments the membrane that contacts theskin can comprise a polyethylene (PE) membrane. In some embodiments themembrane that contacts the skin can comprise a vinyl chloride copolymeror terpolymer. In some embodiments the membrane that contacts the skincan comprise any type of polymeric film. In some embodiments themembrane that contacts the skin can comprise a polyethersulfone (PES)compound. In some embodiments the membrane that contacts the skin cancomprise a polyolefin. In some embodiments the membrane that contactsthe skin can comprise a silicone matrix with a rate-controllingmembrane.

In some embodiments the pore size of the transdermal membrane isselected to achieve a desired permeation rate of the bioactive agent. Insome embodiments the average pore diameter of the transdermal membraneis about 0.02 μm to about 0.10 μm. In some embodiments the average porediameter of the transdermal membrane is about 0.02 μm to about 0.085 μm.In some embodiments the average pore diameter of the transdermalmembrane is about 0.02 μm to about 0.070 μm. In some embodiments theaverage pore diameter of the transdermal membrane is about 0.02 μm toabout 0.060 μm. In some embodiments the average pore diameter of thetransdermal membrane is about 0.02 μm to about 0.050 μm. In someembodiments the average pore diameter of the transdermal membrane isabout 0.03 μm to about 0.050 μm. In some embodiments the average porediameter of the transdermal membrane is about 0.04 μm to about 0.050 μm.

The porosity of the transdermal membrane can be expressed as apercentage of open surface area for the plurality of pores to thesurface area of the membrane configured to contact the skin. In someembodiments the porosity of the transdermal membrane is about 25% toabout 75%. In some embodiments the porosity of the transdermal membraneis about 30% to about 70%. In some embodiments the porosity of thetransdermal membrane is about 30% to about 65%. In some embodiments theporosity of the transdermal membrane is about 30% to about 60%. In someembodiments the porosity of the transdermal membrane is about 35% toabout 60%. In some embodiments the porosity of the transdermal membraneis about 35% to about 65%. In some embodiments the porosity of thetransdermal membrane is about 35% to about 55%. In some embodiments theporosity of the transdermal membrane is about 35% to about 50%. In someembodiments the porosity of the transdermal membrane is about 40% toabout 50%. In some embodiments the porosity of the transdermal membraneis about 40% to about 45%. In some embodiments the porosity of thetransdermal membrane is about 40% to about 42%.

In some embodiments the transdermal membrane can be treated to changethe wettability or other properties of the membrane. For example, thetransdermal membrane can be surfactant treated, plasma treated, or othertreatments to change wettability and other properties of the transdermalmembrane.

The geometry of the plurality of pores of the transdermal membrane canvary. In some embodiments the plurality of pores can have a circularcross-section. In some embodiments the plurality of pores of themembrane have a non-circular cross section. In some cases the pluralityof pores of the membrane can include longitudinal slits having alongitudinal cross section. A plurality of different pore shapes andsizes can also be used in some cases.

The transdermal membrane can have a surface area selected to deliver thedesired amount of drug or bioactive agent to the skin of the wearer. Insome embodiments the transdermal membrane has a surface area that isless than about 15 cm². In some embodiments the membrane has a surfacearea that is less than about 10 cm². In some embodiments the membranehas a surface area that is from about 15 cm² to about 30 cm².

Specific examples of membrane materials that can be used in the drugdelivery systems disclosed herein include a variety of differentCelgard® products.

In some embodiments the transdermal membrane is Celgard® 2325. Celgard®2325 has an average pore size of 0.028 μm and a porosity of 39%.

In some embodiments the transdermal membrane is Celgard® 2340. Celgard®2340 has an average pore size of 0.035 μm and a porosity of 45%.

In some embodiments the transdermal membrane is Celgard® 2400. Celgard®2400 has an average pore size of 0.043 μm and a porosity of 41%.

In some embodiments the transdermal membrane is Celgard® 2500. Celgard®2500 has an average pore size of 0.064 μm and a porosity of 55%.

In some embodiments the transdermal membrane is Celgard® 2325. Celgard®2325 has an average pore size of 0.028 μm and a porosity of 39%.

In some embodiments the transdermal membrane is Celgard® 3400. Celgard®3400 has an average pore size of 0.043 μm and a porosity of 41%.Celgard® 3400 is surfactant coated to improve wettability of themembrane.

In some embodiments the transdermal membrane is Celgard® 3401. Celgard®3401 has an average pore size of 0.043 μm and a porosity of 41%.Celgard® 3401 is surfactant coated to improve wettability of themembrane.

In some embodiments the transdermal membrane is Celgard® 3500. Celgard®3500 has an average pore size of 0.064 μm and a porosity of 55%.Celgard® 3500 is surfactant coated to improve wettability of themembrane.

In some embodiments the transdermal membrane is Celgard® 3501. Celgard®3501 has an average pore size of 0.064 μm and a porosity of 55%.Celgard® 3501 is surfactant coated to improve wettability of themembrane.

In some embodiments the transdermal membrane is Celgard® 4550. Celgard®4550 has an average pore size of 0.035 μm and a porosity of 45%.Celgard® 4550 includes a trilayer construction ofpolypropylene/polyethylene/polypropylene.

In some embodiments the transdermal membrane is Celgard® 4560. Celgard®4560 has an average pore size of 0.064 μm and a porosity of 55%.

In some embodiments the transdermal membrane is Celgard® 5550. Celgard®5550 has an average pore size of 0.064 μm and a porosity of 55%.

The vapor permeable membrane can be made of a material with a porosityand pore size selected to minimize or substantially block the flow ofliquid phase solvent and liquid phase drug while permitting vapor phasesolvent to pass through. In some embodiments the vapor permeablemembrane has an average pore size of less than about 10 microns (μm). Insome embodiments the vapor permeable membrane has an average pore sizeof about 0.1 microns to about 10 microns.

The porosity can also be selected to achieve the desired vapor flowcharacteristics across the vapor permeable membrane. The porosity can beexpressed as a ratio of the open surface area of the plurality of poresof the vapor permeable membrane to the surface area of the vaporpermeable membrane. In some embodiments the porosity is less than about50%. In some embodiments the porosity is from about 25% to about 50%. Insome embodiments the porosity is from about 25% to about 40%. In someembodiments the porosity is from about 30% to about 40%.

In some embodiments the vapor permeable membrane is made out of PTFE. Insome embodiments the vapor permeable membrane can be POREX®. POREX® hasan average pore size of 5 microns and a porosity of about 35%.

A variety of different drug delivery system configurations areillustrated in FIGS. 4-14. The systems can include one or morereservoirs, such as reservoir 38 and bolus chamber 46, configured tohold the bioactive agent and/or the solvent composition. The agentreservoir can refer to either of the bolus/dose reservoir and mainreservoir.

A dose of the bioactive agent can be provided to the space between thetransdermal membrane and the vapor permeable membrane. The system isconfigured to move the bioactive agent in the solvent solution from theagent reservoir to a virtual space between the vapor permeable membraneand the transdermal membrane. The dose is preferably provided such thatthe dose quickly and evenly spreads across the transdermal membrane. Thetransdermal membrane can be treated to improve wettability of themembrane. In some cases the transdermal membrane can be tautly spread toreduce the likelihood of pooling of the dose or poor distribution of thedose across the transdermal membrane. In some embodiments the dose ofthe bioactive agent and solvent solution is provided to a substantiallycentrally located section of the membrane. In some embodiments the doseof the bioactive agent and solvent solution is provided to an off-centersection of the membrane. In some embodiments the dose of the bioactiveagent and solvent solution is provided through multiple orifices ontothe membrane.

The distribution of the dose across the membrane can also be improved byproviding a specific volume of the dose per surface area of thetransdermal membrane. In some embodiments the dose of the bioactiveagent and solvent solution has a volume of less than about 250 μL per 10cm² of surface area of the membrane. In some embodiments the dose of thebioactive agent and solvent solution has a volume of between about 75 μLto about 250 μL per 10 cm² of surface area of the membrane. In someembodiments the dose of the bioactive agent and solvent solution has avolume of less than about 150 μL per 10 cm² of surface area of themembrane.

The systems can include enough bioactive agent for a single dose, a fullday's worth of dosing, or enough doses to cover multiple days. Thebioactive drug and solvent composition can be provided in a mainreservoir and moved to a dosing/bolus chamber prior to drug delivery asdescribed herein.

The volume of the agent reservoir (e.g. reservoir 38) can vary based onthe dosage size, number of doses, and concentration of the bioactiveagent. The agent reservoir can have a volume of less than about 3 ml. Insome embodiments the agent reservoir has a volume of about 5 μL to about3 ml. In some embodiments the agent reservoir can have a volume of lessthan about 2 ml. In some embodiments the agent reservoir can have avolume of less than about 1 ml. In some embodiments the agent reservoirhas a volume of less than about 750 μL. In some embodiments the agentreservoir has a volume of less than about 500 μL. In some embodimentsthe agent reservoir has a volume of less than about 250 μL.

A second reservoir (e.g. bolus/bolus chamber) can have a volume of lessthan 3 ml. In some embodiments the second reservoir has a volume of lessthan about 1 ml. In some embodiments the second reservoir has a volumeof less than about 750 μL. In some embodiments the second reservoir hasa volume of less than about 500 μL. In some embodiments the secondreservoir has a volume of less than about 250 μL.

The agent reservoir can be provided in a removable and disposableportion. In some embodiments the disposable portion includes both theagent reservoir and the second reservoir (e.g., dosing/bolus chamber).The systems can include a sensor configured to determine when theremovable portion is connected to the bioactive agent delivery system.

The systems include a control unit configured to control the bioactiveagent delivery system to provide a dose of the bioactive agent andsolvent solution from the agent reservoir to the membrane. The controlunit can be configured to carry out any of the steps described herein.For example, the control unit can provide a bio-synchronous drugdelivery protocol to the wearer of the bioactive agent delivery system.

The control unit can be configured to record a time of administration ofthe bioactive agent, a dosage amount of the bioactive agent, and a timeat which dosing ceased. In some embodiments the system can include awireless data transfer unit configured to wirelessly transmit the timeof administration of the bioactive agent, the dosage amount of thebioactive agent, and the time at which dosing ceased to a remote networkor device.

In some embodiments the systems can provide a psychological support tothe wearer. The psychological support can be an encouraging messaging oradvice about dealing with cravings. The control unit can be configuredto gather wearer data during the bio-synchronous drug delivery protocoland to provide the psychological support based on specific patient data.Patient data can include patient emotional state data, such as cravings,and patient compliance. Patient compliance can include determiningwhether the drug delivery device was removed, a treatment in a drugdelivery protocol was missed, or if the drug delivery protocol wasinterrupted.

The drug delivery systems described herein can include a solventrecovery chamber. The vapor phase solvent solution can be passed in thevapor phase through the vapor permeable membrane into the solventrecovery chamber of the drug delivery device. The movement of the vaporphase solvent from the space between the transdermal membrane and vaporpermeable membrane can increase the concentration of the remaining drugor bioactive agent to help promote the drug or bioactive agentpermeation across the transdermal membrane.

The solvent recovery chamber can include a desiccant, absorbentmaterial, or external vent. In some embodiments the vapor phase solventcondenses and is collected within the solvent recovery chamber by thedesiccant or absorbent material. In some embodiments blotting paper isused as an absorbent material. The solvent recovery chamber can be partof the disposable unit.

FIGS. 30-32 illustrate different transdermal membrane materials beingtested with different solvents and solvent compositions. Solutions ofwater and different alcohols, including isopropanol, ethanol, andmethanol were tested. The water to alcohol content was varied between0/100 and 100/0 (by v/v) and tested with different membrane materials.For the tests 1.6 mL of solution was injected into the area between thetransdermal membrane and the vapor permeable membrane. The transdermalmembrane was observed to view the wetting and permeability of themembrane to the tested solvent solution. The membranes were observedapproximately 90 seconds after providing the solvent solution to thespace between the transdermal membrane and the vapor permeable membrane.A white membrane indicates no permeation of the solvent solution acrossthe membrane. A darkening of the membrane preceded permeation. Threedifferent transdermal membrane materials were tested including Celgard®2400 (FIG. 30), Celgard® 2500 (FIG. 31), and Celgard® 3501 (FIG. 32).Celgard® 2400 has an average pore diameter of about 0.041 μm and aporosity of 41%. Celgard® 2500 has an average pore diameter of about0.064 μm and a porosity of 55%. Celgard® 3501 has an average porediameter of about 0.064 μm and a porosity of 55%.

FIG. 30 shows results for 100% isopropanol, 80% isopropanol/20% water,60% isopropanol/40% water, 40% isopropanol/60% water, 20%isopropanol/80% water, and 100% water. The 100% water and 20%isopropanol solutions showed white membranes indicative of nopermeation. For the isopropanol and water solutions permeation wasvisible for 40% isopropanol and greater. Liquid visibly passed throughthe membrane for 80% isopropanol compositions and greater. FIG. 30 alsoshows results for 100% ethanol (EtOH), 80% ethanol/20% water, 60%ethanol/40% water, 50% ethanol/50% water, 40% ethanol/60% water, and 20%ethanol/80% water. No permeation was observed for 20% ethanol/80% water.Some permeation was observed for 40% ethanol/60% water. 50% ethanol/50%water showed a good balance between permeation and permeation rate. FIG.30 also shows results for 100% methanol (MeOH), 80% methanol/20% water,60% methanol/40% water, 40% methanol/60% water, and 20% methanol/80%water. No permeation was observed for 20% methanol, 40% methanol, and60% methanol compositions. Some permeation was observed for 80% methanoland 100% methanol. For Celgard® 2400, the composition of 50% ethanol and50% water (v/v) exhibited the best combination of permeation andpermeation rate.

FIG. 31 shows results Celgard® 2500 for 100% isopropanol, 80%isopropanol/20% water, 60% isopropanol/40% water, 40% isopropanol/60%water, and 20% isopropanol/80% water. The 20% isopropanol and 40%isopropanol compositions showed minimal permeation. For the isopropanoland water solutions permeation was visible for 60% isopropanol andgreater. Liquid visibly passed through the membrane for 80% isopropanolcompositions and greater. FIG. 31 also shows results for 100% ethanol(EtOH), 80% ethanol/20% water, 60% ethanol/40% water, 40% ethanol/60%water, and 20% ethanol/80% water. Minimal permeation was observed for20% ethanol/80% water. Some permeation was observed for 40% ethanol/60%water. FIG. 31 also shows results for 100% methanol (MeOH), 80%methanol/20% water, 60% methanol/40% water, 40% methanol/60% water, and20% methanol/80% water. No permeation was observed for 20% methanol, 40%methanol, and 60% methanol compositions. Some permeation was observedfor 80% methanol and 100% methanol.

FIG. 32 shows results for Celgard® 3501 for 100% isopropanol, 80%isopropanol/20% water, 60% isopropanol/40% water, 40% isopropanol/60%water, and 20% isopropanol/80% water. All of the isopropanol solutionsshowed permeation of the Celgard® 3501 membrane. FIG. 32 also showsresults for 100% ethanol (EtOH), 80% ethanol/20% water, 60% ethanol/40%water, 40% ethanol/60% water, and 20% ethanol/80% water. All ethanolcompositions showed permeation for Celgard® 3501. FIG. 32 also showsresults for 100% methanol (MeOH), 80% methanol/20% water, 60%methanol/40% water, 40% methanol/60% water, and 20% methanol/80% water.All compositions of methanol showed permeation with Celgard® 3501. Theincreased permeation with Celgard® 3501 could be due to a combination ofthe larger pore size and surfactant coating.

As for additional details pertinent to the present invention, materialsand manufacturing techniques may be employed as within the level ofthose with skill in the relevant art. The same may hold true withrespect to method-based aspects of the invention in terms of additionalacts commonly or logically employed. Also, it is contemplated that anyoptional feature of the inventive variations described may be set forthand claimed independently, or in combination with any one or more of thefeatures described herein. Likewise, reference to a singular item,includes the possibility that there are plural of the same itemspresent. More specifically, as used herein and in the appended claims,the singular forms “a,” “and,” “said,” and “the” include pluralreferents unless the context clearly dictates otherwise. It is furthernoted that the claims may be drafted to exclude any optional element. Assuch, this statement is intended to serve as antecedent basis for use ofsuch exclusive terminology as “solely,” “only” and the like inconnection with the recitation of claim elements, or use of a “negative”limitation. Unless defined otherwise herein, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. The breadth of the present invention is not to be limited bythe subject specification, but rather only by the plain meaning of theclaim terms employed. The term “about” when used with a quantity ormeasurement means ±10%.

What is claimed is:
 1. A two-part bioactive agent delivery system, thesystem comprising: a disposable part comprising: an agent reservoir, abolus chamber, a piston movably disposed in the agent reservoir, thepiston configured to transfer bioactive agent from the agent reservoirto the bolus chamber, and a transdermal patch include connection withthe bolus chamber and configured to transdermally deliver the bioactiveagent to the user; a reusable part comprising a power source and controlelectronics, the control electronics configured to deliver bioactiveagent from the bolus chamber to the transdermal patch; and a springextending from the piston, the spring configured to become at leastpartially loaded when the disposable part is connected to the reusablepart and the agent reservoir contains the bioactive agent.
 2. Thetwo-part bioactive agent delivery system of claim 1, further comprisinga valve between the agent reservoir and the bolus chamber, the valveconfigured to allow the bioactive agent to move from the agent reservoirto the bolus chamber.
 3. The two-part bioactive agent delivery system ofclaim 2, wherein the valve is further configured to allow the bioactiveagent to move from the bolus chamber to the transdermal patch.
 4. Thetwo-part bioactive agent delivery system of claim 2, wherein the valveis a rotatable valve having a range of motion between 60° and 90°. 5.The two-part bioactive agent delivery system of claim 1, furthercomprising a second piston movably disposed in the bolus chamber, thesecond piston configured to transfer bioactive agent from the boluschamber to the transdermal patch.
 6. The two-part bioactive agentdelivery system of claim 5, further comprising a second spring extendingfrom the second piston, the second spring configured to become at leastpartially loaded when the bioactive agent is in the bolus chamber. 7.The two-part bioactive agent delivery system of claim 6, the boluschamber piston configured to move and load the second spring whenpressurized bioactive agent enters the bolus chamber from the agentreservoir through the valve.
 8. The two-part bioactive agent deliverysystem of claim 1, wherein the transdermal patch comprises apolypropylene membrane.
 9. The two-part bioactive agent delivery systemof claim 1, further comprising a connection indicator operativelyconnected to the control electronics to provide an indication that thereusable part has been connected to the disposable part.
 10. Thetwo-part bioactive agent delivery system of claim 1, wherein the springis disposed in the disposable part prior to connecting the disposablepart to the reusable part.
 11. The two-part bioactive agent deliverysystem of claim 1, wherein the spring is disposed in the reusable partprior to connecting the disposable part to the reusable part.
 12. Thetwo-part bioactive agent delivery system of claim 1, further comprisinga solvent recovery element configured to receive gaseous phase solventfrom the transdermal patch.
 13. The two-part bioactive agent deliverysystem of claim 1, further comprising a vapor permeable barrier in thedisposable part adjacent to the transdermal patch.
 14. The two-partbioactive agent delivery system of claim 1, wherein the agent reservoirand bolus chamber are configured to contain the bioactive agent and asolvent solution comprising alcohol and water.
 15. The two-partbioactive agent delivery system of claim 14, wherein the solventsolution has a ratio of water to alcohol of about 40:60 to about 60:40.